Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[CH3:19][N:20]([CH3:30])[CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1.CN(C)CCCC1C=NC=CC=1>[Ru](=O)=O>[CH:7]1[C:6]2[CH:5]([N:26]3[CH2:27][CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][CH2:21][N:20]([CH3:30])[CH3:19])[CH2:25]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCCC1CCCNC1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Agent: O=[Ru]=O
Agent: CN(C)CCCc1cccnc1
Product: CN(C)CCCC1CCCN(C2c3ccccc3Oc3ccccc32)C1

Procedure:
By the procedure of Example 1, reacting 9-acetoxyxanthene with 3-(3-dimethylaminopropyl)piperidine [prepared by hydrogenating 3-(3-dimethylaminopropyl)pyridine in the presence of ruthenium dioxide by the procedure of Example 12] gives 1-(9-xanthenyl)-3-[3-(dimethylamino)propyl]piperidine.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:20]([OH:34])[CH2:21][NH:22][C@@H:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.[ClH:35]>[Pd].O1CCCC1>[ClH:35].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:20]([OH:34])[CH2:21][NH:22][C@@H:23]([CH3:33])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: COc1ccc(C[C@H](C)NC[C@@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C[C@H](C)NC[C@@H](O)c2ccc(O)c3[nH]c(=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 916 mg of 8-benzyloxy-5-{(1S)-1-hydroxy-2-[N-((1S)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril, 100 mg of 10% palladium-charcoal, 2 ml of 1N hydrochloric acid and 20 ml of tetrahydrofuran is shaken at room temperature at an atmospheric pressure under a hydrogen atmosphere for 2 hours. Insoluble materials are collected by filtration and washed with an aqueous 10% ethanol solution. The filtrate and washings are combined, and the combined solution is concentrated under reduced pressure to remove solvent. The residue is crystallized with a mixture of methanol and ether, and crystalline precipitates are collected by filtration. 623 mg of 8-hydroxy-5-{(1S)-1-hydroxy-2-[N-((1S)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride are obtained as colorless crystals. Yield: 77%
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]1[NH:19][C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[S:21].[OH-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O.O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]1[NH:19][C:20](=[N:22][C:23]([O:25][CH3:26])=[O:24])[S:21][CH2:31][CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CCCSC1=C(Cc2ccccc2)C(NC(=S)NC(=O)OC)C(=N)C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C=CCSC(=NC(=O)OC)NC1C(=N)C=CC(SCCC)=C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 1-iminophenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (1.0 g.) in acetone (30 ml.) and water (10 ml.) there is added aqueous sodium hydroxide (0.21 g.). The mixture is stirred at room temperature for one hour (a solution forms 20 minutes after the addition of sodium hydroxide) and to it there is added allyl bromide (0.36 g.). The solution is stirred at room temperature for two hours and is then poured into water (300 ml.). The mixture is stirred at room temperature for 24 hours and is vacuum filtered. The tacky yellow solid is stirred in hexane (50 ml.) and is filtered to yield 0.35 g. of 1-iminohexylmethyl-2-(3-carbomethoxy-S-isothioureido)-4-propylthiobenzene, m.p. 70°-72° C.
Reaction SMILES: Cl.Cl.[CH3:3][C@@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][S:5]1.[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([F:39])[CH:33]=1)[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C@@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])[C:28]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@@H:4]([CH3:3])[S:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:29])=[CH:33][C:34]=1[F:39]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Reactant: C[C@H]1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)c(F)c4)NC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of (R)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (30 mg, 0.097 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoic acid (31 mg, 0.097 mmol) in CH2Cl2 (5 mL) and triethylamine (1 mL) was added HBTU (37 mg, 0.097 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL) and washed with water (5×50 mL). The organic phase was dried and concentrated. The residue was subject to silica gel chromatography, eluting with CH2Cl2/MeOH (50:1) to give tert-butyl (R)-3-(4-chloro-3-fluorophenyl)-1-(4-((R)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (44 mg, 85%). MS (APCI+) [M+H]+ 536.
Reaction SMILES: [N+](C1C=C(C=CC=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:8])([O-])=O.[Cl:22]C1C=CC=CC=1>>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7]([Cl:22])=[O:8])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: Clc1ccccc1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1

Procedure:
For example, 3,3'-dinitro-4,4'-dichlorobenzophenone can be prepared in a yield of 95 to 98% by nitrating 4,4'-dichlorobenzophenone [E. R. Kofanov et al., J. Org. Chem. USSR, 15, 98-100 (1979)]. 5,3'-Dinitro-2,4'-dichlorobenzophenone can be prepared in a high yield by nitrating 2,4'-dichlorobenzophenone [E. H. Faith et al., J. Am. Chem. Soc., 77, 543 (1955)]. 3,3'-Dinitro-4-chlorobenzophenone can be prepared in a high yield by nitrating 4-chlorobenzophenone [G. S. Mironov et al., J. Org. Chem. USSR, 8, 1538 (1972)]. 3,4'-Dinitro-4-chlorobenzophenone can be prepared by nitrating 4-halogeno-4'-nitrobenzophenone obtained by the condensation reaction between p-nitrobenzoyl chloride and chlorobenzene [P. T. Montagne et al., Ber., 49, 2267-2270 (1916); G. S. Mironov et al., J. Org. Chem. USSR, 8, 1538-1543 (1972)]. 3,3'-Dinitro-6,4'-dichlorobenzophenone can be prepared in a high yield by nitrating 2,4'-dichlorobenzophenone obtained by the condensation reaction between 2-chlorobenzoyl chloride and chlorobenzene [H. F. Faith et al., J. Am. Chem. Soc., 77, 543 (1955)].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH:23]([O:26][CH3:27])[O:24][CH3:25].CNC1CCCCC1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)(Cl)Cl.[Cu](I)I.CO.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:21]4[CH:20]=[N:19][CH:18]=[CH:17][C:22]=4[CH:23]([O:26][CH3:27])[O:24][CH3:25])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: COC(OC)c1ccncc1Br
Agent: I[Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(OC)c1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 52.8 %

Procedure:
Using the same reaction conditions and work up as described in Example 1, step-3,1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 515 mg, 2.35 mmol) was refluxed with 3-bromo-4-dimethoxymethyl-pyridine (600 mg, 2.584 mmol), copper iodide (44.7 mg, 0.2312 mmol), N,N′-dimethyl-cyclohexane-1,2-diamine (80.8 mg, 0.7405 mmol), potassium phosphate (1.4 g, 7.046 mmol) and 1,4-dioxane (20 mL) at 110° C. for 12 hours to afford the crude product. The reaction was monitored by TLC (10% MeOH in chloroform). Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 460 mg of the product (52.9% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)=[N:11][CH:12]=[C:13]([CH:15]=[CH:16][CH2:17][CH2:18][CH3:19])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(NN)(=O)=O)=CC=1.[ClH:39]>>[ClH:39].[CH2:1]([O:8][C:9]1[C:10]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC=Cc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cl
Product: CCCCCc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Yield: 37.7 %

Procedure:
N-(3-(benzyloxy)-5-(pent-1-enyl)pyridin-2-yl)-4-methylthiazol-2-amine (360 mg, 0.98 mmol) and 4-methylbenzenesulfonohydrazide (733 mg, 3.94 mmol) were reacted according to Example 93 to afford the title compound (150.2 mg, 37.7% yield) as a white solid after HCl salt formation. 1H NMR (DMSO-d6) 11.24 (bs, 1H), 7.83 (d, 1H), 7.61 (d, 2H), 7.56 (d, 2H), 7.44-7.32 (m, 3H), 6.87 (s, 1H), 5.34 (s, 2H), 2.57 (t, 2H), 2.33 (s, 3H), 1.57 (m, 2H), 1.35-1.18 (m, 4H), 0.85 (t, 3H). Mass spectrum (apci) m/z=368.1 (M+H-HCl).
Reaction SMILES: [CH2:1]([CH:7]([CH2:39][CH2:40][CH2:41][CH2:42]CCCC)[CH2:8][O:9][C:10]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[C:16]([O:22][CH2:23][CH:24]([CH2:33][CH2:34]CCCC)[CH2:25][CH2:26][CH2:27][CH2:28]CCCC)=[C:12]2[S:13][CH:14]=[CH:15][C:11]=12)[CH2:2]CCCC.C([Li])CCC.[CH3:52][Sn:53](Cl)([CH3:55])[CH3:54].O>C1COCC1>[CH2:1]([CH:7]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:8][O:9][C:10]1[C:18]2[S:19][C:20]([Sn:53]([CH3:55])([CH3:54])[CH3:52])=[CH:21][C:17]=2[C:16]([O:22][CH2:23][CH:24]([CH2:33][CH3:34])[CH2:25][CH2:26][CH2:27][CH3:28])=[C:12]2[S:13][C:14]([Sn:53]([CH3:55])([CH3:54])[CH3:52])=[CH:15][C:11]=12)[CH3:2]
Reactant: CCCCCCCCC(CCCCCC)COc1c2ccsc2c(OCC(CCCCCC)CCCCCCCC)c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(CC)COc1c2cc([Sn](C)(C)C)sc2c(OCC(CC)CCCC)c2cc([Sn](C)(C)C)sc12
Temperature: -70 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
4,8-Bis[(2-hexyldecyl)oxy]-benzo[1,2-b:4,5-b′]dithiophene (0.80 g, 1.19 mmol) was dissolved in dry THF (10 mL) under nitrogen. The solution was cooled to −70° C. and butyllithium (1.0 mL, 2.M solution in hexanes, 2.5 mmol) was added dropwise. The reaction was allowed to warm to room temperature over 2 hours and cooled back to −78° C. Trimethyltin chloride (0.61 g, 3.0 mmol) was added. The reaction was allowed to warm to room temperature and stirred under nitrogen overnight. Water (50 mL) was added and the reaction was extracted with ether. Organic layer was separated and dried over Na2SO4. Solvent was removed under vacuum. To the residue was added ethanol (10 mL) and the suspension was stirred overnight. The resulting white solids were collected by filtration and dried under vacuum to afford the product 4,8-bis[(2-ethylhexyl)oxy]-2,6-bis(1,1,1-trimethyl-stannanyl)benzo[1,2-b:4,5-b′]dithiophene (0.58 g, 49%). 1H NMR (CDCl3, 500 MHz) δ=7.52 (m, 2H), 4.17 (d, J=5.0 Hz, 4H), 1.86 (m, 2H), 1.67 (m, 4H), 1.28-1.55 (m, 44H), 0.86 (m, 12H), 0.55 (m, 18H).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH2:10][C:11]([OH:15])(O)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.O=P(Cl)(Cl)Cl.CN([CH:24]=[O:25])C>>[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:24]=[O:25])=[C:11]([OH:15])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: OC1(O)C=C2C(=CC1)CCCN2CCF
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c(cc1O)N(CCF)CCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
290 mg (1.48 mmol) 1-(2-Fluoro-ethyl)-7-hydroxy-1,2,3,4-tetrahydro-quinolin-7-ol are dissolved in 5 mL DMF. 0.15 mL POCl3 are added dropwise at 0° C. The reaction mixture is slowly heated to 50° C., stirred an additional 3 h at this temperature, then cooled to RT and extracted with ethyl acetate and an aqueous saturated solution of sodium bicarbonate. The combined organic phases are washed with brine, dried over sodium sulphate and evaporated. The residue is column chromatographed (silica gel, ethyl acetate/petroleum ether 1:2) to yield 200 mg (60%) desired product as a brown solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.Cl.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:27])[CH2:22][CH2:21]1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:27])[C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH2:22][CH2:21]2)=[O:13])=[C:9]([O:16][CH3:17])[CH:8]=1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Agent: Cl
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCC(C(=O)c2ccc(C)cc2)CC1
Yield: 10.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (285 mg) described in Preparation Example 19 and (piperidin-4-yl)(p-tolyl)methanone hydrochloride (252 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (52 mg) was obtained.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][C:14]1([C:20]([O:22]CC)=O)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O.[H-].[Na+]>>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=3)[CH2:15]2)[C:20]1=[O:22]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCOC(=O)C1(CCNc2cnccc2C)CCCNC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccncc1N1CCC2(CCCN(c3ccc(C(F)(F)F)cn3)C2)C1=O
Reaction time: 8 h

Procedure:
A mixture of ethyl 3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-3-carboxylate trihydrochloride (42.8 mg, 0.000107 mol), 2-chloro-5-(trifluoromethyl)pyridine (23 mg, 0.00013 mol) and N,N-diisopropylethylamine (0.056 mL, 0.00032 mol) in N-methylpyrrolidinone (0.8 mL, 0.008 mol) was irradiated with microwaves to 180° C. for 20 min. Sodium hydride (30.0 mg) was then added to the above solution and the mixture was stirred overnight. The product was purified by prep-HPLC. LC-MS: 391.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:9][CH3:10])[CH2:1][CH3:2])[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CCN(CC)CCCCN
Product: CCN(CC)CCCCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 4-diethylaminobutylamine (reference example 93h) and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 510 (M+H)+.
Reaction SMILES: ClC(OCC(C)C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:27](O)=[O:28])=[C:23]([CH3:26])[CH:24]=3)[O:19][C:18](=[O:30])[CH:17]=2)=[CH:12][CH:11]=1.CCN(CC)CC.[BH4-].[Na+]>C1COCC1.O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH2:27][OH:28])=[C:23]([CH3:26])[CH:24]=3)[O:19][C:18](=[O:30])[CH:17]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc2c(-c3ccc(F)cc3)cc(=O)oc2cc1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc2c(-c3ccc(F)cc3)cc(=O)oc2cc1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isobutyl chloroformate (0.775 mL, 5.97 mmol) was added dropwise to 4-(4-fluorophenyl)-6-methyl-2-oxo-2H-chromene-7-carboxylic acid (0.594 g, 1.99 mmol) and Et3N (1.11 mL, 7.96 mmol) in THF (13 mL) at 0° C. After 1 h, a freshly prepared solution of NaBH4 0.377 g, 9.96 mmol) in water (10 mL) was added rapidly. The reaction mixture was stirred at 0° C. for 1 h, quenched using saturated. NH4Cl and extracted with EtOAc (3×). The combined organic extracts were washed with 1 N HCl, 5% NaHCO3 and brine, dried (Na2SO4) and concentrated. The residue was subjected to column chromatography on silica gel (EtOAc—CHCl3, 30:70, then 35:65, then 40:60) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 7.65 (m, 2H), 7.53 (s, 1H), 7.38 (m, 2H), 7.26 (s, 1H), 6.30 (s, 1H), 4.76 (d, 2H), 4.55 (t, 1H), 2.26 (s, 3H).
Reaction SMILES: [Na].[K].[C:3]1(=[O:18])[N:7]([CH2:8][S:9](O)(=[O:11])=[O:10])[C:6](=[O:13])[C:5]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:4]12.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[C:3]1(=[O:18])[N:7]([CH2:8][S:9]([Cl:20])(=[O:11])=[O:10])[C:6](=[O:13])[C:5]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:4]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1CS(=O)(=O)O
Agent: [K]
Agent: [Na]
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CS(=O)(=O)Cl
Reaction time: 1.5 h

Procedure:
To 41.7 g. (0.15 mol.) of phthalimidomethanesulfonic acid potassium sodium 220 ml. of dry benzene is added 22.5 g. (0.132 mol.) of phosphorus pentachloride. The reaction mixture is refluxed on a steam bath for one hour, then an additional 22.5 g. of phosphorus pentachloride is added and heating is continued for 1.5 hours. The reaction mixture is evaporated to dryness, crushed ice is added to the residue and the slurry is filtered. The product is washed with water to give phthalimidomethanesulfonyl chloride.
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7](CC)[CH:6]=1>C(OCC)C>[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:2]#[N:1])=[CH:7][CH:6]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: N#CBr
Solvent: CCOCC
Product: N#CNc1ccc(Br)cc1
Reaction time: 72 h
Yield: 24.8 %

Procedure:
A mixture of cyanogen bromide (5.0 g, 47 mmol) and 4-bromo-2-ethylaniline (20.6 g, 103 mmol) in diethylether (150 mL) was stirred for 3 days under nitrogen atmosphere. The amine hydrobromide was filtered off, and the filtrate was concentrated in vacuo at room temperature and triturated with hexane to give 4-bromophenylcyanamide (2.3 g, 10%) as an off white solid. HRMS: calcd for C9H9BrN2+H+, 225.00218; found (ESI-FTMS, [M+H]+), 225.00277.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:21]1=[O:37]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:18])([F:19])[F:17])=[CH:11][N:10]=2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][C:30]([OH:32])=[O:31])[C:21]1=[O:37]
Reactant: Cn1c(=O)n(CC(=O)OC(C)(C)C)c(=O)n(-c2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc2Br)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(CC(=O)O)c(=O)n(-c2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc2Br)c1=O
Temperature: 25 °C

Procedure:
A solution of tert-butyl 3-{2-bromo-5-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]oxy}phenyl}tetrahydro-5-methyl- 2,4,6-trioxo-s-triazine-1(2H)-acetate (7.00 g, 0.012 mol) in trifluoroacetic acid (40 mL) is refluxed for 2.5 hours, cooled to room temperature and concentrated in vacuo to give the title product which is identified by 1HNMR spectral analysis.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]([CH3:37])[C@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:38][C:39]1(C)[O:44]C(=O)C[C:41](=O)[O:40]1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.COC(C)(C)C>[CH3:41][O:40][C:39](=[O:44])[CH2:38][C:25](=[O:27])[C@H:24]([N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])[CH3:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)[C@@H](Cc1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (2.9011 g, 13.9 mmol) in toluene (3 ml) is added to a stirred mixture of (R)-2-(tert-butoxycarbonyl-methyl-amino)-3-(3,4-dichloro-phenyl)-propionic acid (1, 4.179 g, 12 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (2, 1.7815 g, 12.36 mmol) and dimethyl-pyridin-4-yl-amine (2.0943 g, 16.8 mmol) in toluene (32 ml) at 29-31° C. over a period of approx. 1 hour. Toluene (1 ml) is used for rinsing. Stirring at 29-31° C. is continued for approx. 3 hours. After cooling to ca. 0° C., a 25% w/w solution of potassium hydrogen sulfate (approx. 9 ml) is added to the suspension at −2° C./2° C., until pH 2-3 is reached. Stirring is stopped and the layers are allowed to separate. The mixture is slowly stirred and filtrated cold (0-5° C.) and the filter cake is rinsed with toluene (12 ml, 0-5° C.). The layers of the filtrate are allowed to separate at approx. 0-5° C. The lower, aqueous layer is separated. The upper, organic layer, containing the intermediate [(R)-1-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-2-oxo-ethyl]-methyl-carbamic acid tert-butyl ester (3) is passed through a filter charged with anhydrous sodium sulfate (5 g) at 0-5° C. and the filtrate is added to a reactor, containing methanol (18 ml, 20-25° C.). The filter cake is rinsed with toluene (5 ml) and the filtrate is also added to the reactor. The resulting solution is heated (mantle temperature ca. 68° C.) and stirred at approx. 63° C. for approx. 4 hours, then concentrated at a mantle temperature of approx. 50° C. under reduced pressure to obtain an oily residue, which is dissolved in tert-butyl methyl ether (24 ml) at normal pressure and a mantle temperature of ca. 50° C., then concentrated again under reduced pressure to obtain (R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-1-oxo-pentanoic acid methyl ester (4) as an oily residue. The residue is dissolved again in tert butyl methyl ether (24 ml) at normal pressure and a mantle temperature of 50° C., then cooled to 18-22° C. and used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[N+:16]([O-])=O.[Cl-].[NH4+].O>[Fe].CO>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[NH2:16]
Reactant: COC(=O)c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(OC)c(OCCCl)cc1N

Procedure:
A mixture of 68.2 g (235.4 mmol) of 4-(2-chloro-ethoxy)-5-methoxy-2-nitro-benzoic acid methyl ester and 52.6 g (941.8 mmol) of iron was mechanically stirred at reflux in a mixture containing 62.9 g ammonium chloride, 393 ml water, and 1021 ml methanol for 15 hr. The mixture was concentrated and mixed with ethyl acetate. The organic solution was washed with water and saturated sodium bicarbonate. The solution was dried over magnesium sulfate and filtered through a short column of silica gel. The solution was concentrated to 200 ml and diluted with 250 of hot hexane. After standing 47.7 g of the tide compound was obtained as a solid: mass spectrum (electrospray, m/e) M+H 259.8.