Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][CH:20]=[O:21])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.Cl([O-])=[O:34].[Na+].O.P([O-])(O)(O)=O.[Na+]>O1CCCC1.C(O)(C)(C)C.O.[Au]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([OH:34])=[O:21])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: O=CCn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O
Agent: [Au]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A solution of crude [5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetaldehyde (15.30 g, 42.11 mmol) in 198.0 mL of tetrahydrofuran, t-butyl alcohol, and 2-methyl-2-butene (1:1:1.3, 0.21 M) was cooled to 0° C. The solution was then slowly added a solution of sodium chlorite (29.94 g, 331.1 mmol) and sodium dihydrogenphosphate monohydrate (35.42 g, 256.7 mmol) in 102.0 mL of water (3.2 M based on sodium chlorite). The resulting gold colored, biphasic solution was stirred for 10 minutes and the cold bath was removed. The reaction was stirred for 1 hour at room temperature. The volatiles were removed under reduced pressure. The resulting solution was diluted with water (200 mL) and the pH was adjusted to 3 by addition of sat NaHCO3 and 1 N HCl. The aqueous solution was extracted by tetrahydrofuran, dichloromethane (1:2, 4×180 mL). The combined organic solutions were dried (MgSO4), filtered, and concentrated to give the crude product. Purification by trituration with ethyl ether gave an 88% yield of [5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid as a white solid: 1H NMR (300 MHz, d-DMSO) δ 13.34 (br s, 1H), 9.03 (s, 1H), 7.57-7.34 (m, 10H), 5.23 (s, 2H), 4.56 (s, 2H); 13C NMR (75 MHz, d-DMSO) δ 169.4, 158.0, 154.6, 154.3, 137.1, 134.8, 130.9, 129.4, 129.1, 128.78, 128.72, 128.50, 125.5, 67.0, 48.8; HRMS (EI) calcd for C20H18N3O5 380.1246, found 380.1246.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2cc(C#N)cn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cnn(-c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
To a solution of 1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (115 mg, 0.575 mmol) in dichloromethane (5 mL) was added boron tribromide (431 mg, 1.73 mmol) at −10° C. The reaction was then warmed to room temperature and stirred for 16 hours. The reaction was quenched with methanol (0.5 mL) and water (5 mL), and extracted with ethyl acetate (3×15 mL). The combined organics were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated to give 1-(4-hydroxyphenyl)-1H-pyrazole-4-carbonitrile (46 mg, 43%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 9.89 (s, 1H), 9.12 (s, 1H), 8.27 (s, 1H), 7.62 (d, J=9.2 Hz, 2H), 6.90 (d, J=9.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:19](=[O:20])[NH:18][N:17]=[C:7]3[CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]4[NH:12][C:13]([CH:14]=1)=[C:5]2[C:6]=43.[CH3:21][N:22]([CH2:24][CH2:25]Cl)[CH3:23].CN(C)CCN1C2CC(C)(C)CC3=NNC(=O)C4C(C=23)=C1C=CC=4>>[CH3:21][N:22]([CH3:23])[CH2:24][CH2:25][N:12]1[C:11]2[CH2:10][C:9]([CH3:16])([CH3:15])[CH2:8][C:7]3=[N:17][NH:18][C:19](=[O:20])[C:4]4[C:5]([C:6]=23)=[C:13]1[CH:14]=[C:2]([F:1])[CH:3]=4
Reactant: CC1(C)CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1
Reactant: CN(C)CCCl
Agent: CN(C)CCn1c2c3c4c(cccc41)C(=O)NN=C3CC(C)(C)C2
Product: CN(C)CCn1c2c3c4c(cc(F)cc41)C(=O)NN=C3CC(C)(C)C2

Procedure:
Compound 40 was prepared from 8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one and N,N-dimethylamino-2-chloroethane according to the procedures similar to those for Compound 28. 1H NMR (DMSO-d6) δ 10.1 (s, 1H), 7.56 (dd, 1H, J=9.6, 1.8 Hz), 7.21 (dd, 1H, J=10.2, 1.8 Hz), 4.22 (m, 2H), 2.74 (s, 2H), 2.51 (m, 2H), 2.26 (s, 2H), 2.17 (s, 6H), and 1.06 (s, 6H). MS (ESI) m/e [M+1]+ 343.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>CO.[Ni]>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCCCCCOc1ccccc1N

Procedure:
1-(Hexyloxy)-2-nitrobenzene, 61.28 g (0.27 mol) is dissolved in 700 ml of methanol, 3 g Raney nickel is added and the mixture exposed to hydrogen gas until the required amount of hydrogen is absorbed. The methanol solution is filtered and concentrated in vacuo and the residue distilled to give 50 g of 2-(hexyloxy)benzenamine; bp 145°-148° C. at 4 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:35]2[NH:39][C:38]([C:40]3[CH:45]=[N:44][CH:43]=[CH:42][N:41]=3)=[CH:37][CH:36]=2)[CH2:13][C@H:14]2[CH2:34][CH2:33][C:16]3(O[C@H](C4C=CC=CC=4)[C@@H](C4C=CC=CC=4)[O:17]3)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:35]2[NH:39][C:38]([C:40]3[CH:45]=[N:44][CH:43]=[CH:42][N:41]=3)=[CH:37][CH:36]=2)[CH2:13][C@H:14]2[CH2:34][CH2:33][C:16](=[O:17])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3cnccn3)[nH]2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(=O)C2)c2ccc(-c3cnccn3)[nH]2)cc1Cl
Temperature: 50 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To a solution of 2-(5-{1-[3-chloro-4-(methylsulfonyl)phenyl]-2-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]ethyl}-1H-pyrrol-2-yl)pyrazine (94.3 mg) in tetrahydrofuran (1 mL) was added 1M hydrochloric acid (1 mL), and the mixture was stirred at 50° C. for 24 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (44.7 mg, yield 68%) was obtained as a white amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 444 (MH+).
Reaction SMILES: ClC1C=C(C=C(F)C=1)N[C:6]1[C:15]2[C:10](=CC(F)=C([N+]([O-])=O)[CH:14]=2)N=CN=1.N1(CCCO)CCOCC1.[C:34]([OH:38])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:15]([CH3:14])([CH3:6])[CH3:10])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)O
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(F)cc(Cl)c3)ncnc2cc1F
Agent: OCCCN1CCOCC1
Product: CC(C)(C)OC(C)(C)C

Procedure:
This reaction was all the more surprising since the tert.-butyl alcohol present in the reaction mixture does not react with (V) in an analogous manner to the 3-morpholin-4-yl-propan-1 -ol (VI) to give the corresponding tert.-butyl ether.
Reaction SMILES: [C:1]([C@@:9]1([OH:37])[C@@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:16]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:15]([CH2:35][OH:36])[O:14][C@H:10]1[S:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>ClCCl>[C:44]([O:36][CH2:35][C@H:15]1[O:14][C@@H:10]([S:11][CH2:12][CH3:13])[C@:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([OH:37])[C@@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:46])[CH3:45]
Reactant: CCS[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OC(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS[C@@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OC(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethyl 2,3-O-dibenzoyl-4-O-benzyl-1-thio-β-D-glucohexopyranoside (hdo-- 9:1) (200 mg, 0.38 mmol) was dissolved in an ice-cooled mixture of pyridine and acetic anhydride (1:1, 6 ml). The mixture was stirred and attained room temperature overnight. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate and water, dried over sodium sulphate. the solvents were removed under reduced pressure and the residue was subjected to flash chromatography on silica gel (toluene-acetonitrile 6:1) to yield 204 mg, 93% of hdo-- 9:2.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][C:5]1([CH3:11])[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[CH2:12]([O:16][C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[CH:19][N:18]=1)[C:13]#[C:14][CH3:15].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([O:16][C:17]1[C:22]([F:23])=[C:21]([N:7]2[CH2:8][CH2:9][CH2:10][C:5]([CH3:11])([CH3:4])[CH2:6]2)[N:20]=[CH:19][N:18]=1)[C:13]#[C:14][CH3:15]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: CC1(C)CCCNC1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(N2CCCC(C)(C)C2)c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
0.12 g of sodium hydride (60% oil suspention) was suspended in 2 ml of tetrahydrofuran. 0.18 g of 3,3-dimethylpiperidine hydrochloride and 0.20 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine were added therein, and the mixture was stirred for 1 hour at 60° C. After the reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.05 g of 4-(2-butynyloxy)-6-(3,3-dimethylpiperidino)-5-fluoropyrimidine (hereinafter, referred to as Compound (32)).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:11]1[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[N:14][N:13]=[N:12]1)[CH3:21]
Reactant: CCOC(=O)CCl
Reactant: c1cc2c(cc1-c1nnn[nH]1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1nnnc1-c1ccc2c(c1)OCO2

Procedure:
A mixture of 5-(1,3-benzodioxol-5-yl)-1H-tetrazole (10 mmol), ethyl chloroacetate (10 mmol) and potassium carbonate (15 mmol) in dry acetone (100 mL) was refluxed for 24 h. The reaction mixture was filtered, the solvent was distilled. The crude ester thus obtained was purified by recrystallization from ethanol.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]3(O)[CH2:18][CH:17]([C:19]4[N:23]([CH3:24])[C:22]5[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=5[N:20]=4)[CH2:16]3)[CH:9]=2)[N:3]=1.CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]3([F:36])[CH2:18][CH:17]([C:19]4[N:23]([CH3:24])[C:22]5[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=5[N:20]=4)[CH2:16]3)[CH:9]=2)[N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1nc(-n2nc(C)nc2C)cc(C2(O)CC(c3nc4ccccc4n3C)C2)n1
Solvent: ClCCl
Product: Cc1nc(-n2nc(C)nc2C)cc(C2(F)CC(c3nc4ccccc4n3C)C2)n1
Temperature: 25 °C

Procedure:
To a solution of Example 1 (20 mg, 0.051 mmol) in dry CH2Cl2 (2 mL) was added DAST (16 mg, 0.102 mmol) at −78° C. The solution was allowed to warm to room temperature over 1 h at which time LCMS indicated the reaction was complete. The reaction mixture was concentrated and the crude residue was purified by reverse-phase chromatography (5-30% MeOH/H2O) to give Example 2 as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.96-7.86 (m, 3H), 7.74-7.60 (m, 2H), 4.69-4.52 (m, 1H), 4.05 (s, 3H), 3.51-3.34 (m, 4H), 2.91 (s, 3H), 2.55 (s, 3H), 2.41 (s, 3H). MS: m/z=392.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.C(OCC)(=O)C>[CH2:25]([O:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc2nc3ccc4c(OCc5ccccc5)cccc4c3nc12

Procedure:
A mixture of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (80 mg), sodium hydroxide (34 mg) and benzyl bromide (100 μL) in ethanol (2 mL) was heated to reflux for 4 hours. The reaction mixture was then cooled, diluted with ethyl acetate, washed with dilute acid, dried (MgSO4) and the solvent removed in vacuo to yield the crude title compound as a brown solid (50 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:7][CH2:6]2.Cl.Cl[CH2:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:37][CH:38]=1)[CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:7][CH2:6]2
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1cccc(C2CCc3cc(OC)ccc3N2)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(C2CCc3cc(OC)ccc3N2Cc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 60 °C

Procedure:
To a solution of 6-methoxy-2-(3-methoxy-phenyl)-1,2,3,4-tetrahydro-quinoline (20 mg, 0.074 mmol) in THF (1.5 mL) at room temperature is added 1-[2-(4-chloromethyl-phenoxy)-ethyl]-piperidine hydrochloride (PCT Int. Appl. Publ. No. WO 99/19293) (43 mg, 0.149 mmol) followed by phosphazene P1 base (150 mg). The mixture is then heated to 60° C. for 18 h. The crude product is then loaded on a silica gel column and is eluted with 0–100% EtOAc/hexanes to yield 6-methoxy-2-(3-methoxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline which is contaminated with an unidentified byproduct.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].ClC1C=CC=C(C(OO)=[O:39])C=1>O1CCCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][N+:17]([O-:39])=[CH:18][CH:19]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3cc[n+]([O-])cc3)c(=O)c1Br)C2(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (50 mg, 0.105 mmol) and m-chloroperbenzoic acid (35 mg, 0.112 mmol) suspended in tetrahydrofuran (1.5 mL) were stirred at room temperature for 5 minutes and at 80° C. for 30 minutes. After cooling, the reaction solution was concentrated, and the resulting residue was purified by silica gel chromatography (chloroform/methanol=5/1) to give the desired product (49 mg, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(C)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Product: CC(O)c1cc(CBr)ccc1[N+](=O)[O-]

Procedure:
Compound 2 is synthesized in two steps from 1-(5-methyl-2-nitrophenyl) ethanone (1), which can be obtained as described by Doppler et al. (1979) Helv. Chem. Acta 62:291-303. Specifically, the ring methyl group is brominated using N-bromosuccinimide and then the benzylic ketone is reduced to an alcohol. Those procedures are described below.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[CH:21]1([C:24]([NH2:32])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([NH:32][C:12](=[O:14])[C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][CH2:4][CH2:5]3)=[CH:11][N:10]=2)([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:25])[CH2:23][CH2:22]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3(F)CCC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 285a) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and the racemate was separated into its enantiomers by preparative chiral HPLC (Chiralpak AD, ethanol/heptane). The title compound was the second enantiomer collected; MS (ESI, m/z): 443.3 (M+H+).
Reaction SMILES: Br[C:2]1[C:3](=[O:33])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:60][C:61]1[CH:62]=[C:63](B(O)O)[CH:64]=[CH:65][C:66]=1[O:67][CH3:68]>>[F:60][C:61]1[CH:62]=[C:63]([C:2]2[C:3](=[O:33])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]2)[CH:5]=3)[CH:64]=[CH:65][C:66]=1[O:67][CH3:68]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Yield: 77 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[3-(4-(methylsulfonyl)piperazin-1-yl)propoxy]-1H-inden-1-one obtained in Step 1 of Example 108 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][SH:29])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:1].[ClH:14].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[SH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:31][CH:30]=3)[CH2:21][CH2:22]2)[OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC(Nc1ccc(Cl)c(Cl)c1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 52.2 %

Procedure:
The procedure described in Example 2 was followed, using 1.6 g of 3,4-dichlorophenyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.9 g of triethylamine and 50 ml of methylene chloride, to give 1.2 g (26% of theory) of N-(3,4-dichlorophenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 227°-230° C.
Reaction SMILES: N[C:2]1C=CC(C)=CC=1.O=P(Cl)(Cl)Cl.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>CO>[CH3:14][N:15]([CH3:2])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1
Reactant: Cc1ccc(N)cc1
Reactant: CNc1ccc(C)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: Cc1ccc(N(C)C)cc1
Temperature: 280 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of 749 g of p-toluidine, 1,008 g of methanol and 7.9 g of POCl3 is introduced into a 3 l autoclave with an up-and-down stirrer. After closing the autoclave, it is heated up to 280° C. and kept at this temperature for about 3 hours. A pressure of about 60 bar is thereby established. A crude oil composed of <1% of p-toluidine, 1% of N-methyl-p-toluidine and 94% of N,N-dimethyl-p-toluidine is obtained.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)=[O:11])[N:9]=1)[C:2]([NH2:4])=[NH:3].[ClH:26]>>[ClH:26].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[O:11])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2csc(NC(=N)N)n2)cc1
Agent: Cl
Product: N=C(N)Nc1nc(C(=O)Nc2ccc(OCC(=O)O)cc2)cs1

Procedure:
227 mg of ethyl {4-[(2-guanidino-thiazole-4-carbonyl)-amino]-phenoxy}-acetate are stirred for 3 days at RT in 25% hydrochloric acid. The precipitate is filtered off under suction, washed with water, triturated in methanol, filtered off under suction and dried. There are obtained 165 mg of [4-[(2-guanidino-thiazole-4-carbonyl)- amino]-phenoxy]-acetic acid hydrochloride (1:1); m.p. 278° C., MS: 336 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[Cl:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[NH:42][CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]=2[CH:44]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:42]2[CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]3[CH:44]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]2=3)=[O:16])=[CH:12][C:11]=1[Cl:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1Cl
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(Cl)c1)C2
Reaction time: 3 h
Yield: 63 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-3-chloro-benzoic acid from Example E2b (568 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DMAP (244 mg, 2.0 mmol), DIEA (11.0 ml, 6.0 mmol) then WSCD (500 mg, 2.6 mmol). The mixture was stirred for 3 h then 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (430 mg, 1.8 mmol) was added. The mixture was stirred for 4 days then washed with saturated NaHCO3, brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (570 mg, 63%).