Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([S:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[C:8]([CH3:19])[CH:7]=1)=[O:5])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:11]([CH3:12])=[C:10]2[C:9](=[C:8]([CH3:19])[CH:7]=1)[S:13][CH2:14][CH2:15][C:16]2=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)c(SCCC(=O)O)cc1C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)c1cc(C)c2c(c1C)C(=O)CCS2
Temperature: 40 °C
Yield: 86.3 %

Procedure:
21.5 Grams (64 mmol) of 3-(4-ethoxycarbonyl-2,5-dimethylphenylthio)propionic acid was added to 100 g of a 20 wt % P2O5 -containing polyphosphoric acid at room temperature, and then the mixture was stirred under heat at 40° C. for 2 hours. After allowed to cool, the reaction mixture was gradually added to ice water and extracted with ethyl acetate, and an organic layer was washed with a 1 wt % sodium carbonate aqueous solution twice, with water twice and with a saturated sodium chloride aqueous solution once, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 14.6 g (yield 86%) of the titled compound.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:9](=[O:26])[N:10]([C:22]([CH3:25])([CH3:24])[CH3:23])[N:11]=[CH:12][C:13]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(Cl)Cl.O>[C:27]1([S:33]([NH:7][C:8]2[C:9](=[O:26])[N:10]([C:22]([CH3:23])([CH3:25])[CH3:24])[N:11]=[CH:12][C:13]=2[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)n1ncc(NCc2ccncc2)c(N)c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)n1ncc(NCc2ccncc2)c(NS(=O)(=O)c2ccccc2)c1=O
Reaction time: 0.33 h

Procedure:
Into 6 ml of a pyridine solution of 0.55 g of 4-amino-2-tert-butyl-5-(4-pyridylmethylamino)pyridazin-3-(2H)-one, 0.36 g of benzenesulfonyl chloride was dropwise added at room temperature. The mixture was reacted overnight, and 80 ml of water and 100 ml of methylene chloride were added to the system. The mixture was adjusted to pH4 with dilute hydrochloric acid under cooling with ice, and then stirred for 20 minutes. The organic layer was dried over anhydrous sodium sulfate and then concentrated. To the residue, 4 ml of ethyl acetate was added, and the mixture was mashed, whereupon crystals were collected by filtration. The obtained crystals were subjected to column chromatography, and using an eluent (n-hexane:ethyl acetate=1:5), 0.30 g of the desired product (Compound No. 32) having a melting point of from 189° to 190° C., was obtained.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]=[CH:3][CH:4]([OH:6])C.B(F)(F)F.CCO[CH2:15][CH3:16].[CH:17]12[CH2:26][CH:23]([CH2:24][CH2:25]1)C(=C)[C:18]2([CH3:20])[CH3:19]>>[C:15]12([CH3:16])[C:18]([CH3:20])([CH3:19])[CH:17]([CH2:26][CH2:23]1)[CH2:25][CH:24]2[O:6][CH2:4][CH:3]=[CH:2][CH2:1][OH:7]
Reactant: C=C1C2CCC(C2)C1(C)C
Reactant: CC(O)C=CCO
Reactant: CCOCC
Agent: FB(F)F
Product: CC1(C)C2CCC1(C)C(OCC=CCO)C2
Temperature: 80 °C

Procedure:
Into a two liter reaction vessel equipped with stirrer, thermometer, heating mantel and reflux condenser is placed 1000 grams (7.35 moles) of 2-pentene-1,4-diol and 15 grams of boron trifluoride etherate. The reaction mass is then heated to 80° C. Over a period of two hours while maintaining the reaction mass at 80° C., 500 grams (3.7 moles) of camphene is added. The reaction is continued to be stirred at 80° C. for a period of 12.5 hours after the feeding of the camphene.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12.[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([NH2:35])=[CH:30][CH:29]=2>>[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([NH:35][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[N:16]=[C:15]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])[CH:14]=[CH:13][CH:12]=4)[S:10][C:3]=13)=[CH:30][CH:29]=2
Reactant: O=C(c1cccc(-c2cc3nccc(Cl)c3s2)n1)N1CCOCC1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccc(C(=O)N6CCOCC6)n5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from [6-(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyridin-2-yl]-morpholin-4-yl-methanone and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.10 (d, 1H), 7.98 (d, 1H), 7.89 (t, 1H), 7.83 (s, 1H), 7.56 (d, 1H), 7.33 (s, 1H), 7.29 (d, 1H), 6.96 (d, 1H), 6.61 (d, 1H), 6.11 (s, 1H), 3.74 (s, 4H), 3.49 (s, 4H), 2.42 (s, 3H); RP18-HPLC RT: 4.58 minutes; API MS: 470 (M+1).
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([N:27]=[C:28]=[O:29])=[C:18]([F:30])[CH:17]=1.[C:31](=O)([O-])[O-].[K+].[K+].CI>O.O1CCCC1>[Cl:15][C:16]1[C:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([N:27]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[N:3]([CH3:31])[C:28]2=[O:29])=[C:18]([F:30])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CC1(C)Oc2c(Cl)cc(F)c(N=C=O)c2O1
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OC(C)(C)O3)c1=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
A mixture of 0,32 g (0.0079 mole) of sodium hydride and 200 mL of dry tetrahydrofuran was cooled to -20 ° C, and 1.26 g (0.0069 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate was added in a dropwise manner. This mixture was stirred for 10 minutes, and then 1.68 g (0.0069 mole) of 7-chloro-2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl isocyanate was added in a dropwise manner. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature at which it was stirred for one hour. At the conclusion of this period the reaction mixture was heated to 85 ° C. at which it was stirred for approximately 16 hours. Then 0.95 g (0.0069 mole) of potassium carbonate and 1.96 g (0.0138 mole) of methyl iodide were added to the reaction mixture, and it was heated at 75 ° C for seven hours. At the conclusion of this period, water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The extracts were washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated from the filtrate under reduced pressure, leaving a residue. This residue was passed through a column of silica gel, eluting with ethyl acetate:heptane (4:1). Product-containing fractions were combined, and the solvent was evaporated under reduced pressure, leaving 0.58 g of 3-(7-chloro-2,2-dimethyl-5-fluoro- 1,3-benzodioxol-4-yl)-1 -methyl-6-trifluoromethyluracil (Compound 5) as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)(=O)C>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: N#Cc1cccc(Oc2cccc(C(F)(F)F)c2)n1
Solvent: CC(=O)O
Product: NCc1cccc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
3.00 g (11.4 mmol) of 2-(3-trifluoromethylphenyloxy)-6-cyanopyridine were dissolved in 120 ml of acetic acid, 300 mg of Pd (OH)2, 20% on charcoal, were added, and the mixture was hydrogenated at a hydrogen pressure of 17 bar for 3 h at room temperature. The catalyst was then removed by filtration, the organic phase was concentrated and the residue was taken up in water. This solution was washed with ethyl acetate, then adjusted to a pH of 10 using 2 N NaOH, and subjected to repeated extraction with ethyl acetate. The combined organic extracts were dried over MgSO4 and then evaporated to dryness.
Reaction SMILES: C([NH:9][C:10]([NH:12][C@@:13]([C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=1[F:25])([CH3:17])[CH2:14][CH2:15]O)=[S:11])(=O)C1C=CC=CC=1.[ClH:26]>>[ClH:26].[Br:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C@:13]2([CH3:17])[CH2:14][CH2:15][S:11][C:10]([NH2:9])=[N:12]2)[CH:23]=1
Reactant: C[C@@](CCO)(NC(=S)NC(=O)c1ccccc1)c1cc(Br)ccc1F
Agent: Cl
Product: C[C@@]1(c2cc(Br)ccc2F)CCSC(N)=N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (S)-1-benzoyl-3-[1-(5-bromo-2-fluoro-phenyl)-3-hydroxy-1-methyl-propyl]-thiourea (0.79 g, 1.8 mmoles) and aqueous HCl (5 N, 25 mL, 71 mmoles) is warmed to 100° C. After stirring for 6 h, the reaction is cooled to ambient temperature and allowed to stand overnight. The reaction is concentrated under reduced pressure to give crude (S)-4-(5-bromo-2-fluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine hydrochloride [MS (m/z): 303, 305 (M+1)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH:13]1([CH2:18][C:19]2[O:23][N:22]=[C:21]([NH:24][C:25](=[O:31])[C@@H:26]([NH2:30])[CH2:27][CH2:28][CH3:29])[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH:13]1([CH2:18][C:19]2[O:23][N:22]=[C:21]([NH:24][C:25](=[O:31])[C@@H:26]([NH:30][CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[CH2:8]3)[CH2:27][CH2:28][CH3:29])[CH:20]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C1CCc2cc(F)ccc2C1
Reactant: CCC[C@H](N)C(=O)Nc1cc(CC2CCCC2)on1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC[C@H](NC1CCc2cc(F)ccc2C1)C(=O)Nc1cc(CC2CCCC2)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Fluoro-3,4-dihydro-1H-naphthalen-2-one (0.2 mmol) was combined with 2-(S)-Amino-pentanoic acid (5-Cyclopentylmethyl-isoxazol-3-yl)-amide (0.2 mmol) in 2 mL of anhydrous dichloromethane under N2. Sodium triacetoxyborohydride (0.3 mmol) and two drops acetic acid were added and the reaction was stirred at rt for 16 h. The crude solution was then concentrated under reduced pressure and purified through flash chromatography on silica gel to give 2-(S)-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (5-cyclopentylmethyl-isoxazol-3-yl)-amide, LC-MS: retention time 2.0 min, M+1: 414.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:37])[NH:10][CH:11]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]3[CH:25]=[CH:24][S:23]/[C:22]/3=[N:26]\C(=O)OCC=C)[CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.CC1(C)OC(=O)CC(=O)O1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:10][C@@H:11]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]3[CH:25]=[CH:24][S:23][C:22]3=[NH:26])[CH2:16][CH2:15]2)=[O:13])[C:33]([CH3:35])([CH3:34])[CH3:36])=[O:37])=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)/N=c1\sccn1CC1CCN(C(=O)C(NC(=O)Nc2ccc(Cl)cc2)C(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OC(=O)CC(=O)O1
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](NC(=O)Nc1ccc(Cl)cc1)C(=O)N1CCC(Cn2ccsc2=N)CC1
Yield: 50.1 %

Procedure:
Allyl(2Z)-3-(1-(2-(N′-(4-chlorophenyl)ureido)-3,3-dimethylbutyroyl)-4-piperidinyl)methyl-1,3-thiazol-2(3H)-ylidenecarbamate (0.33 g) obtained in Example 139c) and meldrum's acid (0.13 g) were dissolved in THF (10 ml). The solution was deaerated and substituted with argon. Tetrakis(triphenylphosphine)palladium (0.07 g) was added thereto, and mixed under argon atmosphere for 12 hours. The precipitated insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column to obtain the title compound as a pale yellow solid (0.14 g, 51%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:14]1[CH:19]=[CH:18][N:17]=[C:16](S(CCCC)(=O)=O)[N:15]=1)(=[O:4])=[O:3].Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])[CH2:31][CH2:30]1.C(N(C(C)C)C(C)C)C>CCO>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:28][CH:29]2[CH2:30][CH2:31][CH:32]([C:35]([N:37]3[CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:36])[CH2:33][CH2:34]2)[N:15]=1)(=[O:3])=[O:4]
Reactant: CCCCS(=O)(=O)c1nccc(-n2ccc3c(S(C)(=O)=O)cccc32)n1
Reactant: NC1CCC(C(=O)N2CCCC2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CS(=O)(=O)c1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)N3CCCC3)CC2)n1
Temperature: 170 °C
Yield: 29.9 %

Procedure:
4-Methylsulfonyl-1-(2-butylsulfonyl-pyrimidin-4-yl)-1H-indole (250 mg, 0.636 mmol), (4-amino-cyclohexyl)-pyrrolidin-1-yl-methanone hydrochloride (444 mg, 1.91 mmol), ethyl-diisopropylamine (333 μL, 1.91 mmol), and dry EtOH (5 mL) were placed in a vial, sealed, and heated in a microwave reactor at 170° C. for 1 h. The product was concentrated to dryness and purified by column chromatography (5% MeOH in DCM), clear fractions collected and evaporated to dryness, and dried overnight under vacuum. The product was recrystallized from CH3CN and dried under vacuum to provide {4-[4-(4-methanesulfonyl-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-pyrrolidin-1-yl-methanone (Compound 200, 89 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cu][C:12]#[N:13].C(#N)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N#C[Cu]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#CC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 169.1 %

Procedure:
43.8 g (0.1 mol) 3-chlorobenzoyl chloride, 29.1 g (0.13 mol) copper (I) cyanide, and 20 mL acetonitrile in 37 mL toluene was refluxed for 3 hours, and then cooled to room temperature. Insoluble material was filtered and the residue was washed with toluene. The solvent in the resulting filtrate was evaporated under reduced pressure, and the residue was distilled to yield 28 g 3-chlorophenyloxoacetonitrile (yield=68%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][N:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=1[O:35][CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][N:17]=[CH:18][C:11]=2[N:10]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=2[O:35][CH3:36])[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2cnccc2c1=O
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3ccncc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 25 ml round bottomed flask is charged with (2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl)-acetic acid tert-butyl ester (23.9 mg, 0.086 mmol), 2-bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (30.5 mg, 0.095 mmol) and Cs2CO3 (84.6 mg, 0.172 mmol). The mixture is treated with DMF (2 ml) and the solution stirred at RT overnight. Water is added to the mixture giving rise to a solid. This is filtered, dried, and purified via flash column chromatography, eluting with iso-hexane:EtOAc to give the title compound.
Reaction SMILES: [I:1][CH3:2].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:29])[NH:14][C:15]([C:17]2[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[O:16])=[CH:8][CH:7]=1)(=[S:5])[NH2:4]>CC(C)=O>[IH:1].[CH3:2][S:5][C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:29])[NH:14][C:15]([C:17]2[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[O:16])=[CH:8][CH:7]=1)=[NH:4]
Reactant: CI
Reactant: COC(=O)COc1ccc(C(=O)NC(=O)Nc2ccc(C(N)=S)cc2)cc1
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)NC(=O)Nc2ccc(C(=N)SC)cc2)cc1
Product: I
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Iodomethane (5 ml) was added to a stirred suspension of the product of step (b) (550 mg) in acetone (50 ml). The reaction mixture was stirred at ambient temperature for 2 days and then filtered. The collected solid was washed with acetone and dried to give methyl 4-[4-(4-methylthiocarbonimidoylphenyl)allophanoyl]phenoxyacetate, hydroiodide salt (550 mg), as a yellow solid; m.p. 216°-219° C. (decomposes); NMR Spectrum (DMSO-d6) 2.82 (3H, s), 3.71 (3H, s), 4.93 (2H, s), 7.09 (2H, d), 7.91 (4H, m), 8.05 (2H, d), 11.08 (1H, s), 11.28 (1H, s).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH3:16])[CH:6]=1)(=O)C.[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].O>CN1CCCC1=O>[CH3:16][C:12]1[N:11]([C:7]2[CH:6]=[C:5]([NH:4][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])[CH:10]=[CH:9][CH:8]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CC(=O)Nc1cccc(-n2ccnc2C)c1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nccn1-c1cccc(Nc2ccc(I)cc2[N+](=O)[O-])c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 2j from Example 5 (2 g, 9.3 mmol) in dry N-methyl-2-pyrrolidone (20 ml) is added sodium hydride (0.37 g of a 60% dispersion in mineral oil) in portions at 0° C. under nitrogen. The mixture is stirred for 1 hour, the last 30 min. at room-temperature. 1c from Example 1 (2.67 g, 10 mmol) is added and the temperature is raised to 40-50° C. over night. After cooling the mixture is poured into water (100 ml) and extracted with dichloromethane. The organic phase is extracted with 4M hydrochloric acid. The acidic extract is cooled in ice, rendered alkaline by addition of sodium hydroxide (12M) and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is extracted with a mixture of dichloromethane and diethyl ether (1:1). This extract is concentrated under reduced pressure and the residue is dissolved in dimethoxyethane (60 ml). Aqueous sodium hydroxide (28 ml, 1 M) is added and the mixture is stirred at ambient temperature over night. The mixture is poured into water (200 ml) and a small volume of ethanol is added with stirring. The product is filtered off, washed with water and dried to leave 6j (2 g, 51%). Mp 135-136° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](OC(C)C)([CH3:12])[CH3:11].CC(C)=[O:19]>>[CH3:11][C:10]1([CH3:12])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][C:8](=[O:19])[NH:9]1
Reactant: CC(C)=O
Reactant: N#CCc1ccccc1
Reactant: CC(C)OC(C)C
Product: CC1(C)NC(=O)Cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A polyphosphoric acid (200 g) solution of 10 g of phenylacetonitrile was heated at 140° C., and 14.9 g of acetone was dropwise added thereto, taking 1 hour. Further, this was stirred for 1 hour, then cooled, and ice water and diisopropyl ether were added to the reaction liquid. The organic layer was separated, and the aqueous layer was extracted with chloroform. The chloroform layer was washed with aqueous saturated sodium hydrogencarbonate solution, dried with anhydrous magnesium sulfate, and the solvent was evaporated away to obtain 6.22 g of the entitled compound as a brown solid.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14](Cl)([Cl:16])=[O:15].N1C=CC=CC=1>O1CCCC1>[Cl:16][S:14]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:13])[O:9][CH:10]([CH3:11])[CH3:12])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CC(C)OC(=O)Nc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)N(c1ccccc1)S(=O)Cl
Yield: 61.1 %

Procedure:
Eighteen grams isopropyl phenylcarbamate (~0.1 mol) and 14.0 g thionyl chloride (0.12 mol) were dissolved in 50 ml dry tetrahydrofuran and protected from moisture by a calcium chloride tube. Eight grams pyridine (0.1 mol) were added dropwise while the mixture was stirring at a water bath temperature (15°-20° C.). After the addition of pyridine was completed, the mixture was stirred for 12 hours at room temperature. Pyridine hydrochloride was filtered and the solvent was removed under vacuum. The concentrated residue was diluted with hexane and filtered. The hexane was removed under vacuum and the residue was distilled, giving 16.0 g of product distilling at 113-115/0.08 mm. NMR spectrum of the product in chloroform-d-TMS gave the following absorptions: δ7.6-7.2 (m, 5H, phenyl protons), δ5.5-4.9 (m, 1H, CH) and δ1.4-1.3 (d, 6H, C(CH3)2).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[Cl:9][C:10]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:11]=1[NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[ClH:2].[Cl:9][C:10]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:11]=1[N:12]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Clc1ccc(Cl)c(N2CCNCC2)c1
Yield: 13.2 %

Procedure:
7.14 g of bis(2-chloroethyl)amine hydrochloride was suspended in 70 ml of butanol and 6.48 g of 2,5-dichloroaniline was added thereto at room temperature. After heating under reflux for 48 hours, the reaction mixture was cooled and 5.52 g of potassium carbonate was added. After heating under reflux for additional 24 hours, the insoluble matters were filtered off and the filtrate was concentrated. Then the obtained residue was extracted with chloroform and a saturated aqueous solution of sodium hydrogencarbonate. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (100 g, chloroform:methanol=50:1-30:1). The product was converted into hydrochloride by adding a 1N hydrochloric acid/ethanol solution to thereby give 1.41 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[O:6].[Cl:15][C:16]([Cl:21])([Cl:20])C([O-])=O.[Na+].O>CN(C)C=O>[OH:6][CH:5]([C:4]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:16]([Cl:21])([Cl:20])[Cl:15]
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(C(O)C(Cl)(Cl)Cl)cc1OC
Temperature: 25 °C
Reaction time: 9 h
Yield: 86.3 %

Procedure:
In 1.2 l of dimethylformamide, 196 g of 2,4,5-trimethoxybenzaldehyde were dissolved, followed by the addition of 241 g of sodium trichloroacetate salt under ice cooling. The resulting mixture was stirred at room temperature for 9 hours. After the reaction, 2 l of water were added to the reaction mixture under ice cooling. The solid so precipitated was collected by filtration, followed by washing with water and diethyl ether, whereby 272 g of 1-(1-hydroxy-2,2,2-trichloroethyl)-2,4,5-trimethoxybenzene were obtained (yield: 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH2:10])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH3:14].B1C2CCCC1CCC2.[CH:24]([O:27][BH-](OC(C)C)OC(C)C)(C)C.[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:24]=[O:27])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH3:14]
Reactant: C=CCc1ccc(F)c(OC)c1OC
Reactant: CC(C)O[BH-](OC(C)C)OC(C)C
Agent: B1C2CCCC1CCC2
Agent: [K+]
Product: COc1c(F)ccc(CCCC=O)c1OC
Reaction time: 2 h

Procedure:
The product from Example 54 (7.2 g) was treated with 9-BBN (85 ml, 0.5M in THF) at room temperature with stirring for 2 hours. The stirring was stopped and the reaction mixture cooled to 0° then potassium triisopropoxyborohydride (43 ml, 1.0M in THF) was added. Carbon monoxide was bubbled through the reaction mixture for 3 hours, then pH 7 buffer (60 ml) and 30% H2O2 (16 ml) was added with stirring and the reaction was allowed to stir overnight. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was separated, dried and evaporated to afford the desired product as an oil.