Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:29]=[CH:28][C:18]([CH:19]=[N:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])=[CH:17][CH:16]=1.O>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:19]([NH:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])[C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:29][CH:28]=2)=[CH:3][CH:4]=1
Reactant: CC(C)C[C@@H](CO)N=Cc1ccc(F)cc1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@@H](CO)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,4-dibromobenzene (11.4 g, 48.35 mmol) in ether (120 mL) at −30° C. was added n-butyllithium (24.2 mL, 2.0M cyclohexane solution) over 10 minutes. The reaction mixture was stirred for 45 minutes, whereupon a solution of (S)2-[(4-fluorobenzylidene)-amino]-4-methylpentan-1-ol (maximum 2.16 g, 9.67 mmol from the previous step) in ether (30 mL) was added dropwise. After 2 hours, during which the reaction mixture was allowed to warm to 0° C., water (200 mL) was added. The product was extracted with ethyl acetate (150 mL), washed with brine (100 mL), dried over MgSO4, filtered, concentrated in vacuo, and purified on a short plug of silica gel (20% ethyl acetate/hexane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>>[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[CH:17]=[SH:18][CH2:19][CH2:20][NH:21][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: NCCSCc1c(F)cccc1Cl
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCC[SH]=Cc1c(F)cccc1Cl)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(2-chloro-6-fluorobenzylsulfanyl)ethylamine. The product was purified by mass directed purification to give the title compound as a yellow solid. δH (CD3OD): 2.82 (2H, t), 3.64 (2H, t), 3.95 (2H, s), 7.04–7.09 (2H, m), 7.20–7.25 (2H, m), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=398 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH:16](O)[C:15]2[CH:19]=[C:20]([S:22]([NH2:25])(=[O:24])=[O:23])[S:21][C:14]=2[S:13]1(=[O:27])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:28]([N:30](CC)CC)[CH3:29].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N)C>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH:16]([NH:30][CH2:28][CH3:29])[C:15]2[CH:19]=[C:20]([S:22]([NH2:25])(=[O:24])=[O:23])[S:21][C:14]=2[S:13]1(=[O:27])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCCCN1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: CCN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCNC1CN(CCCO[Si](C)(C)C(C)(C)C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of the product of Step D (1.4 g , 3 mmol) and triethylamine (1.7 mL, 12 mmol) in THF (10 mL) at -20° C. was added p-toluenesulfonyl chloride (1.2 g, 6 mmol) and the reaction mixture was stirred at 0° C. for 5 hr. The reaction mixture was cooled to -78° C. at which point ethylamine (10 mL) was added; this mixture was allowed to warm to reflux temperature for 2 hr and then maintained at room temperature for 40 hr. After removing the solvent the crude product was diluted with ethyl acetate (150 mL), washed with water (2×50 mL) and brine (2×50 mL), dried (MgSO4), and evaporated to a syrup which was purified by column chromatography [silica; CH3OH/CH2Cl2 (20:1)] to give 900 mg (64%) as a colorless foam.
Reaction SMILES: [C:1]12([CH2:11][NH:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(CC)CC.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]12([CH2:11][N:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=4)[O:15][C:31]3=[O:33])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Oc1ccc(C(O)CNCC23CC4CC(CC(C4)C2)C3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC(c2ccc(O)cc2)CN1CC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
4-(2-((1-adamantylmethyl)amino)-1-hydroxyethyl)phenol (50 mg, 0.166 mmol) and Et3N (34 mg, 0.33 mmol) were dissolved in dry CH2Cl2 (1 mL) and the solution was cooled to 0° C. Triphosgene (19.7 mg, 0.066 mmol) in dry CH2Cl2 (1 mL) was added dropwise slowly. The mixture was allowed to warm to rt and stirred overnight. The solution was concentrated to give a residue, which was purified by preparative HPLC to afford 3-adamantan-1-ylmethyl-5-(4-hydroxy-phenyl)-oxazolidin-2-one (2.40 mg, 4.4%). 1H NMR: (CDCl3, 400 MHz): δ=1.54 (s, 6H), 1.58-1.65 (d, 3H), 1.66-1.75 (d, 3H), 1.99 (s, 3H), 2.80-2.87 (d, 1H), 3.02-3.08 (d, 1H), 3.50-3.56 (t, 1H), 3.93-4.00 (t, 1H), 5.40-5.48 (t, 1H), 6.82-6.90 (d, 1H), 7.20-7.26 (d, 1H); MS m/z=328
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([OH:14])=[O:13])[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)Cc1cccc2ccncc12
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1cccc2ccncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl 2-(isoquinolin-8-yl)acetate (1.8 g) in DCM (10 mL) was added TFA (10 mL) dropwise. The reaction was stirred at room temperature overnight. After the reaction was complete, the solvent was removed to give a residue which was adjusted to pH 3-4 with aqueous ammonia. The precipitate was filtered off and washed with water. The final product was purified (silica gel coulumn chromatography) to afford 2-(isoquinolin-8-yl)acetic acid as a solid (1.2 g, 87%). LC-MS (0.05% TFA): [M+1]+ 188.1. 1H-NMR (DMSO-d6, 400 MHz): 613.0 (brs, 1H), 9.65 (s, 1H), 8.61 (d, 1H, J=4.8 Hz), 8.16 (d, 1H, J=4.8 Hz), 8.05 (d, 1H, J=6.8 Hz), 7.92 (t, 1H), 7.72 (d, 1H, J=6.8 Hz), 4.29 (s, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O.Cl.[NH2:21][CH:22]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH2:25][N:24]([C:38]([N:40]2[CH2:49][CH2:48][C:43]3([O:47][CH2:46][CH2:45][O:44]3)[CH2:42][CH2:41]2)=[O:39])[CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:14]([NH:21][CH:22]2[CH2:27][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)[CH2:25][N:24]([C:38]([N:40]3[CH2:41][CH2:42][C:43]4([O:47][CH2:46][CH2:45][O:44]4)[CH2:48][CH2:49]3)=[O:39])[CH2:23]2)=[O:16])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.59 ml (3.38 mmol) of N,N′-diisopropylethylamine and 248 mg (1.58 mmol) of 3-chlorobenzoic acid were added to a solution of the compound from Example 62A (500 mg, 1.06 mmol) in N,N′-dimethylformamide (18 ml). After addition of 522 mg (1.37 mmol) of HATU, the mixture was stirred at RT overnight. The reaction mixture was purified directly by preparative HPLC(RP18 column; acetonitrile/water gradient). Yield: 414 mg (67% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)(=[O:27])=[O:26])=[CH:3][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: Nc1ccc(CO)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Nc1ccc(CO)cc1)c1ccccn1
Yield: 47 %

Procedure:
Reaction of (4-Amino-phenyl)-methanol (249 mg, 2.03 mmol), N,N-diisopropylethylamine (294 μL, 1.69 mmol), and pyridine-2-sulfonyl chloride (300 mg, 1.69 mmol) for 1 h at room temperature followed by column chromatography on silica gel (CH2Cl2/MeOH 194:3) gave the title compound (210 mg, 47%) as a red solid. 1H NMR (300 MHz, CDCl3) δ 4.60 (d, 2H, J=6.0 Hz), 7.07 (br s, 1H), 7.15 (d, 2H, J=8.4 Hz), 7.23 (d, 2H, J=8.7 Hz), 7.44-7.48 (m, 1H), 7.83 (ddd, 1H, J=7.5, 7.5, 1.8 Hz), 7.89 (d, 1H, J=7.8 Hz), 8.72 (d, 1H, J=4.5 Hz).
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]([Cl:17])[CH:6]=1)(=O)C.O=S(Cl)Cl.[CH3:22]O>>[Cl:17][C:7]1[CH:6]=[C:5]([OH:4])[C:10]([O:11][CH3:12])=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:22])=[O:15]
Reactant: CO
Reactant: COc1cc(CC(=O)O)c(Cl)cc1OC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(OC)c(O)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of [4-(acetyloxy)-2-chloro-5-methoxyphenyl]acetic acid (670 mg, 2.587 mmol) in 30 mL of MeOH was added dropwise SOCl2 at 0° C. The resulting mixture was stirred at 50˜60° C. overnight and concentrated to dryness. The residue was dissolved in EtOAc (50 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated to give methyl (2-chloro-4-hydroxy-5-methoxyphenyl)acetate. 1H-NMR (400 MHz, CDCl3) δ ppm 6.94 (s, 1H), 6.75 (s, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 3.68 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:4][CH:3]=1.[Br:25]Br.O>C(O)(=O)C>[Br:25][C:8]1[C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[C:6]=2[O:10][C:9]=1[CH3:11]
Reactant: Cc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc(Cl)c2c1Br
Reaction time: 6 h
Yield: 50 %

Procedure:
1.0 g (2.8 mmol) of 3-(4-chloro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 30 ml of acetic acid, and 0.9 g (5.6 mmol) of bromine was dropwise added thereto at room temperature. After completion of the dropwise addition, stirring was carried out at 40° C. for 6 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and 10% aqueous ammonia and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.6 g (yield: 50.0%) of a pale yellow glassy substance. Refractive index: 1.5632 (20° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:20]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])=[O:21])[CH:10]=1
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1F)Nc1cc(Cl)ccc1C(=O)O

Procedure:
2-Amino-4-chlorobenzoic acid (0.3 g), 2-fluorophenylisocyanate (0.2 ml) and triethylamine (0.24 ml) were stirred in toluene (20 ml) for a week. More 2-fluorophenylisocyanate (0.1 ml) was added and stirring continued for another week. The mixture was concentrated to almost dry, water was added and the pH was adjusted to 1 with diluted HCl. Water was decanted and the residue was dissolved in warm 96% EtOH. The pH was adjusted to 1 again with 4N HCl resulting in the precipitation of a solid, which was filtered and dried to give 4-chloro-2-[3-(2-fluoro-phenyl)-ureido]-benzoic acid (0.25 mg). Mp.=195-197° C. 4-Chloro-2-[3-(3-trifluromethyl-phenyl)-ureido]-benzenesulfonamide (Compound 10):
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.[CH:23](OCC)=[O:24]>>[C:13]([C:12]1[CH:21]=[CH:22][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:23]=[O:24])=[CH:10][CH:11]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCOC=O
Product: O=CNc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1

Procedure:
A solution of 4-(2-aminophenylamino)benzophenone (Compound 101 0.29 g, 1.0 mmol) in ethyl formate (5.0 ml, 63 mmol) was refluxed for 16 hours. The reaction mixture was evaporated in vacuo and dissolved i ethyl acetate. The solution was filtered and evaporated in vacuo. The residue was crystallized on the addition of diethyl ether to afford the pure title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][S:14]([C:17]2[CH:22]=[C:21]([C:23]3[C:24]([CH3:30])=[N:25][C:26]([NH2:29])=[N:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[Cl:31])(=[O:16])=[O:15])[CH2:9][CH2:8]1>N1C=CC=CC=1>[NH2:29][C:26]1[N:25]=[C:24]([CH3:30])[C:23]([C:21]2[CH:20]=[CH:19][C:18]([Cl:31])=[C:17]([S:14]([NH:13][CH:10]3[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C:1](=[O:3])[CH3:2])[CH2:12][CH2:11]3)(=[O:16])=[O:15])[CH:22]=2)=[CH:28][N:27]=1
Reactant: CC(=O)Cl
Reactant: Cc1nc(N)ncc1-c1ccc(Cl)c(S(=O)(=O)NC2CCC(CN)CC2)c1
Solvent: c1ccncc1
Product: CC(=O)NCC1CCC(NS(=O)(=O)c2cc(-c3cnc(N)nc3C)ccc2Cl)CC1

Procedure:
Acetyl chloride (0.045 ml, 0.066 mmol) is added to a stirred solution of N-(4-aminomethyl-cyclohexyl)-5-(2-amino-4-methyl-pyrimidin-5-yl)-2-chloro-benzenesulfonamide (Example 3-18) (0.090 g, 0.22 mmol) in dry pyridine (1 ml). After 30 min the reaction mixture is absorbed on silica and the product is purified by chromatography on silica, eluting with ethyl acetate to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([NH:5][CH2:6][CH2:7][OH:8])=[O:4].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1)([O-:13])=[O:12]>N1C=CC=CC=1>[C:21](=[O:22])([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:10])([F:9])[F:1])[O:20][C:17]1[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=1
Reactant: O=C(NCCO)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: O=C(OCCNC(=O)C(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
17 g (0.108 mol) of 2-(trifluoroacetylamino)ethanol are dissolved in 210 ml of pyridine, 21 g of chloroformic acid 4-nitrophenyl ester are added and the mixture is left to stand overnight at room temperature. It is then concentrated, the residue is taken up in methylene chloride and the methylene chloride mixture is washed with ice-water and dried with Na2SO4. After evaporating off the solvent, 33 g of a light-colored oil are obtained.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:17]#[N:18].Cl.C1(C)C=CC(S(O[CH:30]([CH3:37])[CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH2:33]([N:32]([CH2:35][CH3:36])[CH2:31][CH:30]([N:15]1[C:16]2[CH:3]=[C:4]([C:17]#[N:18])[CH:5]=[CH:6][C:7]=2[S:8][C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:37])[CH3:34]
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Reactant: CCN(CC)CC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 110 °C
Reaction time: 7 h

Procedure:
Sodium hydride (19.2 g; in 50% strength dispersion in vaseline) is added in the course of 20 minutes to a solution of 2-phenothiazinecarbonitrile (44.86 g) in N,N-dimethylformamide (600 cc). The mixture obtained is then heated to 110° C., after which the solution of 1-diethylamino-2-propyl p-toluenesulphonate hydrochloride prepared above is added in the course of 35 minutes. The reaction mixture is stirred at 110° C. for 7 hours and then diluted, after being cooled, with ethyl acetate (2 liters). The mixture is washed with distilled water (5 ×1 liter). The organic phase is extracted with 4 N hydrochloric acid (240 cc) and the acid aqueous phase is washed with ethyl acetate (750 cc) and then alkalinized medium is then extracted with ethyl acetate (1250 cc). The organic phase is washed with distilled water (3×300 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is stirred in the presence of ethyl ether (100 cc); a precipitate forms and this is filtered off, and the filtrate is purified by chromatography on a column of silica gel (0.2-0.063 mm) (height: 82 cm; diameter: 4.5 cm), eluting with an 80:20 (by volume) mixture (7 liters) of cyclohexane and ethyl acetate and collecting 100-cc fractions. After concentration to dryness under reduced pressure (30 mm Hg., 4 kPa) at 50° C., 10-[(2RS)-1-diethylamino-2-prop-yl]-2-phenothiazinecarbonitrile (6.76 g) is obtained from fractions 4 to 9, and a mixture (8.5 g) of 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile and 10-[(lRS)-2-diethylamino-1-propyl]-2-phenothiazinecarbonitrile is obtained from fractions 10 to 22. The mixture is purified by chromatography on a column of silica gel (0.2-0.063 mm) (height: 67 cm; diameter: 3.0 cm), eluting with an 85:15 (by volume) mixture (3 liters) cyclohexane and ethyl acetate and collecting 50-cc fractions. Fractions 22 to 29 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-diethylamino2-propyl]-2-phenothiazinecarbonitrile (2.76 g).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[K].C([O:8][CH:9](OCC)[CH:10]([CH:13]=O)[C:11]#[N:12])C.C[O-].[Na+].CO>CCO>[NH2:12][C:11]1[C:10]([CH:9]=[O:8])=[CH:13][N:4]=[C:2]([SH:3])[N:1]=1
Reactant: CCOC(OCC)C(C#N)C=O
Reactant: NC(N)=S
Agent: C[O-]
Agent: [K]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Nc1nc(S)ncc1C=O
Temperature: 50 °C
Yield: 72.3 %

Procedure:
A slurry of thiourea (92.8 g, 1.22 moles) in EtOH (90 mL) was heated under reflux and vigorously stirred. To this slurry was added a suspension of 3,3-diethoxy-2-formylpropionitrile potassium salt (P-5A) (222.20 g, 1.06 moles) in 25% sodium methoxide/MeOH (85.5 mL, 0.37 mole) and EtOH (285 mL) in five aliquots over a 10 minute period, while maintaining reflux conditions (alternatively, the latter slurry may be heated to 50° C. to give a homogenous solution for the addition). An additional portion of EtOH (150 mL) was added to facilitate stirring. The thick slurry became a bright yellow color following the addition and was held under reflux for an additional 1 hour. The mixture was then cooled and evaporated to near dryness on a rotoevaporator. The residue was dissolved in water (940 mL). Crude product was precipitated from solution by the addition of 30% acetic acid (280 mL) and isolated via filtration using a medium frit sintered glass filtration funnel. The cake was washed with water (800 mL). Purification via trituration in hot water (1 L) for 30 minutes, followed by cooling and filtration gave 118.9 grams (72.3%) of product as a bright yellow solid after drying overnight at 60° C. in a vacuum oven (subsequent preparations have demonstrated that this trituration is unnecessary). An HPLC gave purity as 98.67%. 1H-NMR (DMSO-d6) was consistent with the above desired structure (P-5B).
Reaction SMILES: [H-].[Li+].[CH2:3]([N:5]1[C:10](=[O:11])[C:9]2=[N+:12]([O-:15])[O:13][N:14]=[C:8]2[NH:7][C:6]1=[O:16])[CH3:4].Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1>CN(C=O)C>[CH2:3]([N:5]1[C:10](=[O:11])[C:9]2=[N+:12]([O-:15])[O:13][N:14]=[C:8]2[N:7]([CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[C:6]1=[O:16])[CH3:4]
Reactant: ClCc1cccnc1
Reactant: CCn1c(=O)[nH]c2no[n+]([O-])c2c1=O
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(no[n+]2[O-])n(Cc2cccnc2)c1=O
Temperature: 60 °C
Yield: 19.4 %

Procedure:
0.48 g (60 mmol) of lithium hydride is added in portions to a solution of 5.0 g (25 mmol) of 6-ethyl-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione-1-oxide in 250 ml of DMF. The mixture is heated at 60° C. for 15 minutes, then 4.9 g (30 mmol) of 3-picolyl chloride hydrochloride are added and the mixture is heated at 80° C. for 3 hours. It is then largely concentrated, the residue is taken up with ethyl acetate and the mixture is extracted with 10% strength hydrochloric acid. The aqueous extract is neutralised and extracted with ethyl acetate. Relatively readily volatile impurities are removed by distillation in vacuo at 100° C./0.5 mm Hg and the residue is chromatographed. 1.4 g (20%) of 6-ethyl-4-(3-pyridylmethyl)-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione-1-oxide are obtained as a highly viscous oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH:11]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: Clc1ccnc2cn[nH]c12
Product: c1ccc(Nc2ccnc3cn[nH]c23)cc1
Yield: 55 %

Procedure:
A solution of 7-chloro-1H-pyrazolo[4,3-b]pyridine (215 mg, 1.4 mmol) in aniline (1.3 ml) was heated under reflux under nitrogen for 16 h. The mixture was cooled, and the white solid which separated was collected, washed with 60°-80° petrol and water, then dried. The solid was then dissolved in 60% aqueous methanol (25 ml). The solution was filtered, adjusted to pH9 with 10% sodium carbonate solution, and on cooling the product crystallised, to give the title compound as needles (161 mg, 55%), m.p. 222°-224° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:18]([C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH:22]=O)[CH3:19].CO>[Cl-].[Cl-].[Zn+2].C(N(CC)CC)C>[C:13]([C:9]1[N:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:1][CH2:22][C:21]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:20]=3[CH2:18][CH3:19])[C:3]2=[N:11][C:10]=1[CH3:12])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCc1cccc(C)c1C=O
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(C)cn12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3CC)cc(C)cn12
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A mixture of 8-amino-3-carboethoxy-2,6-dimethylimidazo[1,2-a]pyridine (1.4 g, 6 mmol), 2-ethyl-6-methylbenzaldehyde (0.9 g, 6.5 mmol), ZnCl2 (1.0 g, 7.4 mmol), NaB(CN)H3 (0.41 g, 6.5 mmol) and MeOH (30 ml) was refluxed for 5 h. More ZnCl2 (0.2 g) and NaB(CN)H3 (0.1 g) were added. The reaction mixture was refluxed for additional 2 h. Triethylamin (2 ml) was added and the mixture was stirred at R.T for 10 min. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride as eluent. 1.1 g (50%) of the title compound was obtained.