Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(OC(C)C)(OC(C)C)[O:25]C(C)C.C([Li])(C)(C)C.OO>C(OCC)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: OO
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
A stirred solution of 5.40 g (14.1 mmol) (4R,9aR)-7-bromo-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 350 mL diethyl ether was cooled to −100 deg C. and 6.30 mL (5.13 g, 27.7 mmol) triisopropyl borate was added. To this solution, 11.3 mL (16.9 mmol) tert-butyllithium (1.5 M in n-pentane) was added dropwise and the reaction was stirred at this temperature for another 15 min. The reaction was warmed to −75 deg C., stirred for another 15 min., warmed to 0 deg C., stirred again for 15 min. and then 6.85 mL acetic acid (50% in water) and 0.12 g 35% hydrogen peroxide solution were added successively. The cooling bath was removed and the reaction was stirred for 1 h at room temperature. The reaction mixture was extracted with 10% aqueous thiosulfate solution, the organic layer was washed with brine, dried over magnesium sulfate and filtered. The solvent was removed at a rotary evaporator and the residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant to give the compound as a light yellow solid (75.4%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:8]([OH:9])[C@H:7]([OH:10])[C@@H:6]([CH2:11][OH:12])[O:5][CH:3]1[OH:4].[Cl:13][CH2:14][CH2:15][N:16]([N:29]=[O:30])[C:17](=O)[O:18]C1C=CC=CC=1[N+]([O-])=O.C[OH:32]>CS(C)=O.C(Cl)Cl.O1CCCC1>[OH:4][CH:3]1[O:5][C@H:6]([CH2:11][OH:12])[C@@H:7]([OH:10])[C@H:8]([OH:9])[C@@:2]1([NH:1][C:17](=[O:18])[N:16]([CH2:15][CH2:14][Cl:13])[N:29]=[O:30])[OH:32]
Reactant: CO
Reactant: O=NN(CCCl)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=NN(CCCl)C(=O)N[C@]1(O)C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
1.79 g (10 mmol) of 2-amino-2-deoxy-D-glucopyranose is dissolved in a mixture of 10 ml methanol and 5 ml dimethyl sulfoxide, and this solution is added dropwise to a solution prepared by dissolving 3.28 g (12 mmol) of o-nitrophenyl N-(2-chloroethyl)-N-nitrosocarbamate in a mixture of 10 ml methylene chloride and 10 ml tetrahydrofuran, while stirring, at 20°-25° C. over 10 minutes. The resultant mixture is stirred at the same temperature for a further 1.5 hours. The thus reacted solution is concentrated at 40° C. and below, under reduced pressure. The crystalline residue obtained is washed with petroleum ether, dried under reduced pressure, and recrystallized from ethanol to give 2.56 g of 3-(D-glucopyranos-2-yl)-1-(2-chloroethyl)-1-nitrosourea. Yield 81.6%. mp 147°-148° C. (decomp.). Analysis for C9H16N3O7Cl (MW 313.69):
Reaction SMILES: C[C@@]12[C@H]3[C@@H](O)C[C@]4(C)[C@@](O)(C(CO)=O)CC[C@H]4[C@@H]3CCC1=CC(=[O:6])CC2.C(N(CCC)C(=O)CCC(O)=O)CC.[CH:41]1([N:47]=[C:48]=[N:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.ClCCl>N1C=CC=CC=1>[C:48]([NH:47][CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)([NH:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:6]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: CCCN(CCC)C(=O)CCC(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a solution of hydrocortisone (5 g, 0.014 mole) and N,N-di-n-propylsuccinamic acid (2.78 g, 0.014 mole) in 25 ml pyridine at room temperature was added dicyclohexylcarbodiimide (2.85 g, 0.014 mole). After the reaction was stirred 10 minutes, 25 ml dichloromethane was added to it to keep the suspension which had formed sufficiently fluid for stirring. After the reaction was stirred overnight, it was filtered. The residue was washed twice with CH2Cl2 and dried in the air to give 2.46 g (91% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to a residue which was dissolved in 25 ml hot THF. After the THF solution was filtered while hot, the resulting filtrate was diluted to 150 ml with Et2O. The product crystallized overnight and was filtered and dried to give 3.49 g of light brown crystals, which a preliminary NMR showed to be contaminated with solvent. The crystals were dried in vacuo (50° C., 2 hours) to give 2.81 g (37% yield) of the desired product: mp 157°-162° C.; NMR (CDCl3) δ5.64 (s, 1, O=C-CH=), 4.98 (m, 2, O=C-CH2O), 4.46 (m, 1, CHOH), 3.8-4.2 (m, 2, OH), 3.24 (t, 4, J=7 Hz, N CH2), 2.70 (s, 4, OCCH2CH2CO), 1.46 (s, 3, C-CH3), 0.96 (s, 3, C-CH3), 0.94 (m, 6, N(CH2CH2CH3)2), 2.9-0.8 (m, 21, CH, CH2); TLC (silica gel, 10% MeOH/Et2O) Rf 0.56; [α]25D=+127° (C=0.5, dioxane); IR (KBr) 3400 cm-1 (s) (OH), 1730, 1710, 1640 and 1610 cm-1 (s) (C=O).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=3)=[S:30])=[CH:7][CH:6]=1)[CH:18]=[CH:17]2
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: COc1ccc2nc(Sc3ccc(N)cc3)ccc2c1
Product: COc1ccc2nc(Sc3ccc(NC(=S)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)ccc2c1
Yield: 71.8 %

Procedure:
2-(4-aminophenylthio)-6-methoxyquinoline 15.0 mmoles, 4.2 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate 15.0 mmoles, 3.6 g) were reacted according to procedure C to yield 5.6 g, 72% of the title compound. Mass Spec (FD) 519. Calculated for C24H17ClF3 N3OS2 : C, 55.44; H, 3.30; N, 8.08. Found: C, 55.62; H, 3.43; N, 8.27.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:28][O:29][C:30]1[C:31]([O:50][CH3:51])=[CH:32][C:33]2[CH2:34][CH:35]3[CH2:49][NH:48][CH2:47][CH2:46][N:36]3[CH:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:38]=2[CH:39]=1>O1CCCC1.C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31]([O:50][CH3:51])=[CH:32][C:33]2[CH2:34][CH:35]3[CH:49]([C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:48][CH2:47][CH2:46][N:36]3[CH:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:38]=2[CH:39]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNC(C(=O)CNC(=O)OC(C)(C)C)C1C2
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
2-[(tert-Butoxy)carbonylamino]acetic acid (1 g) is dissolved in tetrahydrofuran (4 ml), and thereto are added dropwise triethylamine (0.8 ml) and isobutyl chloroformate (0.8 ml) at −20° C., and the mixture is stirred at −10° C. for 5 minutes. To the mixture is added dropwise a suspension of 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (the compound obtained in Example 1-(6)) (1.6 g) in methylene chloride (15 ml), and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, and extracted with methylene chloride. The extract is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent; chloroform:ethyl acetate=4:1) to give 8,9-dimethoxy-2-(tert-butoxycarbonyl)aminoacetyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (872 mg).
Reaction SMILES: Cl.C(O[C:5](=[NH:7])[CH3:6])C.[F:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1>>[NH:7]=[C:5]([N:15]([C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=1)[NH2:16])[CH3:6]
Reactant: CCOC(C)=N
Reactant: NNC(=O)c1ccc(F)cc1
Agent: Cl
Product: CC(=N)N(N)C(=O)c1ccc(F)cc1

Procedure:
Prepared from 7.2 g (58 mmol) ethylacetimidate hydrochloride and 5.00 g (32 mmol) 4-fluoro-benzoic acid hydrazide analogously to the method described for intermediate product 1, Step a).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Reactant: NC1CC1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NC2CC2)nn1
Yield: 83 %

Procedure:
As described for example 52, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using cyclopropylamine instead of ethanolamine, to the title compound (122 mg, 83%) which was obtained as an off white solid. MS: m/e=369.0 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][CH2:25]Cl>CS(C)=O.O>[CH2:7]([NH:11][CH2:25][CH2:24][CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCNCCCOc1ccc2ccccc2c1
Temperature: 135 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-butylamine (0.34 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 135° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-butyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 112° C., (yield 0.55 gm, 94.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[CH:8][NH:7][CH:6]=1)=[O:4].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[CH:8][N:7]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[CH:13]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]cc1C
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2cc(C)nc3ccccc23)cc1C
Temperature: 80 °C
Reaction time: 60 h

Procedure:
1 mmol (139 mg) of 4-methylpyrrole-3-carboxylic acid methyl ester, 1.1 mmol (195 mg) 4-chloro-2-methyl-quinoline and 1.2 mmol (390 mg) of Cs2CO3 are suspended in 3 mL of dry DMF. The mixture is stirred for 60 h at 80° C. under Argon, allowed to cool to room temperature, and diluted with water (20 mL). Part of the product precipitates and is filtered off. The filtrate is extracted twice with ethyl acetate (20 mL portions). The combined extracts are dried over anhydrous Na2SO4 and evaporated. The residue is combined with the precipitate and purified by prep. HPLC to yield 4-methyl-1-(2-methyl-quinolin-4-yl)-1H-pyrrole-3-carboxylic acid methyl ester (MS molpeak 281 (M+) H, electrospray ionisation)) as an off-white foam after freeze-drying.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:26](=O)([O-])[O-].[Cs+].[Cs+].CI>CS(C)=O>[CH3:1][CH:2]([CH3:25])[CH:3]([N:8]([CH3:26])[C:9]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)C(C(C)C)N(C)C(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Reaction time: 0.08 h

Procedure:
To methyl 3-methyl-2-(5-(4-nitrophenyl)thiazole-2-carboxamido)butanoate (Intermediate 2, step C, 1 g) in DMSO (10 ml), to this cesium carbonate (1.346 gm) was added and the reaction mixture was stirred for 5 minutes. To this, methyliodide (0.258 ml) was added and the reaction mixture was stirred for 1 hour. Reaction mixture was quenched using water. The residue obtained was filtered and dried to obtain the title compound. Yield: 0.870 gm (83%); 1H NMR (DMSO-d6, 300 MHz): δ 8.65 (s, 1H), 8.33 (d, 2H), 8.08 (d, 2H), 6.18-4.75 (d, 1H), 3.68 (s, 3H), 3.46-2.96 (s, 3H), 2.38 (m, 1H), 1.03 (d, 3H), 0.91 (d, 3H); MS (ESI) m/z 378 [M+H]+, 400 [M+Na]+
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[NH:18][CH:19]=[O:20])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].[CH3:23]I>CN(C)C=O.O>[CH3:23][N:18]([C:12]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=1[C:3](=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:19]=[O:20]
Reactant: [H][H]
Reactant: O=CNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 70 %

Procedure:
Sodium hydride (0.8 mole, 38.4 g of 50% in mineral oil) was added to a solution of 197.4 g (0.76 mole) of N-(2-benzoyl-4-chlorophenyl)formamide in 800 ml dimethylformamide. When the evolution of hydrogen ceasedm 184 g of methyl iodide was added dropwise at such a rate that the temperature of the reaction mixture slowly rose to 70°. The reaction mixture was stirred for 90 min., and then poured into 2 l. of water. The aqueous mixture was extracted four times with 300 ml portions of methylene chloride, and the combined extracts were washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was recrystallized from methanol to give 145.4 g (70% yield) of the N-methylformamide as colorless crystals: mp 93.5°-94.5°; 1H nmr (CDCl3) showed two methyl peaks at δ 3.00 and 3.28 ppm (ratio 75:25) and 1H nmr (DMSO-d6) showed two methyl peaks at δ 2.94 and 3.23 ppm (ratio 70:30).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]=[C:13]=[S:14])[C:4]2=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CO.C(Cl)(Cl)Cl>CO.C1COCC1>[C:10]1([CH2:11][NH:12][C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[S:14])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: NCC1CCNCC1
Reactant: S=C=NCc1cccc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: S=C(NCc1cccc2ccccc12)NCC1CCNCC1
Yield: 54 %

Procedure:
To a solution of 1-naphthalenemethylisothiocyanate (2.8 g, 13.6 mmol) in 100 ml of MeOH-THF solution (1:1 mixture) was added 4-aminomethylpiperidine (3.1 ml, 27.0 mmol) in a portion and the resulting solution was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding oily mixture which was subjected to column chromatography (10% MeOH/CHCl3) to yield 2.3 g (48%) of the desired product as an oil.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10][CH3:11])=[S:9].[CH3:18][I:19]>CC(C)=O>[IH:19].[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[N:10][CH3:11])[S:9][CH3:18]
Reactant: CNC(=S)Nc1ccccc1-c1ccccc1
Reactant: CI
Solvent: CC(C)=O
Product: CN=C(Nc1ccccc1-c1ccccc1)SC
Product: I

Procedure:
A mixture of N-(2-biphenylyl)-N'-methylthiourea (10.5 g), methyl iodide (6.8 g) and acetone (75 ml) was heated under reflux for 2.5 hours to give 1-(2-biphenylyl)-2,3-dimethyl-2-thiopseudourea hydriodide.
Reaction SMILES: CC1(C)O[C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH2:11](Cl)[CH3:12].[NH2:14][CH2:15][C:16]([OH:18])=[O:17].C(N(CC)CC)C.C(OCC)(=O)C>C(#N)C>[CH2:11]([O:17][C:16](=[O:18])[CH2:15][NH:14][C:7](=[O:8])[CH2:6][C:4]([OH:5])=[O:3])[CH3:12]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: NCC(=O)O
Reactant: CCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CNC(=O)CC(=O)O
Temperature: 60 °C
Reaction time: 5 h
Yield: 60.6 %

Procedure:
To a solution of Meldrum's acid (10.0 g) in acetonitrile (231 mL), glycine ethyl hydrochloride (14.5 g) and triethylamine (14.1 g) were added and the mixture was stirred at 60° C. for 5 hours. After cooling the mixture to room temperature, ethyl acetate was added and extraction was conducted with a saturated aqueous solution of sodium hydrogencarbonate. To the combined aqueous layers, 1 mol/L hydrochloric acid was added and extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give the titled compound as a colorless solid (7.95 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:12]O2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(=[S:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:12][S:32]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCC2CO2)cc1
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CCCC2CS2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(3-phenylpropyl)oxirane (Example 35b) (2.0 g, 0.0123 mol) and triphenylphosphine sulphide (3.62 g, 0.0123 mol) in toluene (20 ml), trifluoroacetic acid (1.40 g, 0.0123 mol) was added over 5 min. After stirring for 1 hour at room temperature, the reaction mixture was washed with water, sodium hydrogen carbonate solution and again with water. After drying (MgSO4) and removal of solvent at reduced pressure, the product contaminated with triphenylphosphine oxide was isolated as a crystalline mass. Attempted purification of the thiirane resulted in its extensive decomposition and it was therefore used in its crude state.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.FC(F)(F)S(O[CH2:39][C:40]([F:43])([CH3:42])[CH3:41])(=O)=O>>[F:20][C:14]1[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:29]4[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:4][S:3][C:2]([NH2:1])=[N:22]3)[C:18]=2[CH:17]=[C:16]([O:19][CH2:39][C:40]([F:43])([CH3:42])[CH3:41])[CH:15]=1
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccnc1F
Product: CC(C)(F)COc1cc(F)c2c(c1)[C@]1(CSC(N)=N1)c1cc(-c3cccnc3F)ccc1O2

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA14 above, but using (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (prepared as described in Method BB26 and Example 2 but using 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one), 2-fluoropyridin-3-ylboronic acid and 2-fluoro-2-methylpropyl trifluoromethanesulfonate. MS m/z=472.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:25])=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH3:24][C:22]1[NH:21][N:20]=[C:19]([NH:18][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:25])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=3)[N:17]=2)[CH:23]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(Nc2nn(-c3ccc(N)cc3)c(=O)c3ccccc23)n[nH]1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-n2nc(Nc3cc(C)[nH]n3)c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Amino-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-phthalazin-1-one (C-2, 0.050 g, 0.15 mmol) was dissolved in pyridine (1 ml) at 0° C. Acetylchloride (0.024 ml, 0.33 mmol) was added and stirring was continued for 30 min at 0° C. before the mixture was allowed to warm to RT. The solvent was evaporated after 2 h stirring at RT. The residue was diluted in MeOH (1 ml) and treated with conc. NH3 (1 ml). The title compound was obtained after stirring at RT for 24 h and evaporation of the solvents in vacuum (0.016 g, 29%). 1H-NMR: (400 MHz, D6-DMSO) 11.93 (1H, s), 10.08 (1H, s), 9.26 (1H, s), 8.49 (1H, d), 8.36 (1H, d), 7.88-7.98 (2H, m), 7.61-7.69 (4H, m), 6.24 (1H, s), 2.19 (3H, s), 2.08 (3H, s); MS (API+)=375 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:15])[N:6]=[CH:7]2.O.NN>C(O)C.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][CH:2]=[C:3]2[C:8]=1[CH:7]=[N:6][C:5]([CH3:15])=[CH:4]2
Reactant: Cc1cc2c(Br)ccc([N+](=O)[O-])c2cn1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc2cccc(N)c2cn1
Yield: 68.8 %

Procedure:
A catalyst consisting of palladium-on-carbon (3/97 by weight; 5 g) is added to a solution of 5-bromo-3-methyl-8-nitroisoquinoline (10.8 g) in ethanol (200 cc). The suspension is stirred, whilst heating to the reflux temperature under a nitrogen atmosphere, and hydrazine hydrate (25 cc) is added dropwise in the course of 30 minutes. The mixture is then heated under reflux for a further 2 hours. The suspension is filtered hot through diatomaceous silica and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in 0.5 N aqueous hydrochloric acid (200 cc) and the resulting solution is extracted with methylene chloride (2×50 cc). The aqueous phase is then rendered alkaline to pH 10 by addition of sodium hydroxide and is extracted with methylene chloride (3×150 cc). The organic extracts are combined, washed with water, dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. to yield 8-amino-3-methylisoquinoline (4.4 g), which is a beige solid, m.p.=175° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[O:13][CH3:14])#[N:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34]>ClCCl>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[OH:34])=[O:10])=[CH:6][C:5]=1[O:13][CH3:14])#[N:2]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COc1cc(C(=O)O)ccc1CC#N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCCC[C@H]2O)ccc1CC#N
Reaction time: 2 h

Procedure:
The 4-(cyanomethyl)-3-methoxybenzoic acid (0.33 g, 1.7 mmol) was suspended in anhydrous dichloromethane (5 mL) and treated with oxalyl chloride (0.3 mL, 3.5 mmol) followed by few drops of DMF at 22° C. under argon. After 2 h stirring, the resulting solution was concentrated to dryness, dissolved in dichloromethane (5 mL), and added slowly to a solution of trans-2-aminocyclohexanol hydrochloride (0.26 g, 1.7 mmol) and TEA (0.5 mL, 3.5 mmol) in anhydrous dichloromethane (10 mL). After 20 min stirring, filtered off salt, and concentrated to afford 4-(cyanomethyl)-N-[(2R)-2-hydroxycyclohexyl]-3-methoxybenzamide as a yellow solid. MS (ESI) 289 (M+H)+.