Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:44])[CH2:16][N:17]([CH2:27][C:28](=[O:43])[NH:29][CH2:30][CH2:31][O:32][C@@H:33]2[O:41][C@@H:40]([CH3:42])[C@@H:38]([OH:39])[C@@H:36]([OH:37])[C@@H:34]2[OH:35])[C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[B-](F)(F)(F)F.CN(C(O[N:58]1[C:63](=[O:64])[CH2:62][CH2:61][C:59]1=[O:60])=[N+](C)C)C.CCN(C(C)C)C(C)C.CCOCC>CN(C=O)C>[C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:44])[CH2:16][N:17]([CH2:27][C:28](=[O:43])[NH:29][CH2:30][CH2:31][O:32][C@@H:33]2[O:41][C@@H:40]([CH3:42])[C@@H:38]([OH:39])[C@@H:36]([OH:37])[C@@H:34]2[OH:35])[C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][N:58]2[C:63](=[O:64])[CH2:62][CH2:61][C:59]2=[O:60])=[O:24])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)CCCCC(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)CCCCC(=O)ON2C(=O)CCC2=O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6-{bis[2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-2-oxoethyl]amino}-6-oxohexanoic acid (160 mg, 0.250 mmol) in DMF (3.0 mL) at 0° C. was added a solution of TSTU (94 mg, 0.313 mmol) in DMF (2 mL) and, 5 min later, DIPEA (53 μL, 0.300 mmol). After stirring for 1.5 h at 0° C., the mixture was added dropwise to Et2O (30 mL) in a centrifuge tube. After centrifuged for 30 min at 3500 rpm, the supernatant was decanted and the solid residue was dissolved in H2O, which was freeze-dried to give the title product. UPLC Method B: m/e=737 [M+1]; Rt=2.19 min.
Reaction SMILES: [NH2:1][C:2]12[C:8]([CH3:10])([CH3:9])[C:5]([CH3:11])([CH2:6][CH2:7]1)[C:4](=[O:12])[CH2:3]2.Cl[C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH2:21])[C:15]=1[N+:22]([O-:24])=[O:23].CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:16]1[C:15]([N+:22]([O-:24])=[O:23])=[C:14]([NH:1][C:2]23[C:8]([CH3:9])([CH3:10])[C:5]([CH3:11])([CH2:6][CH2:7]2)[C:4](=[O:12])[CH2:3]3)[C:19]([Cl:20])=[CH:18][N:17]=1
Reactant: CC12CCC(N)(CC1=O)C2(C)C
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC12CCC(Nc3c(Cl)cnc(N)c3[N+](=O)[O-])(CC1=O)C2(C)C
Temperature: 60 °C
Yield: 100 %

Procedure:
4-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (8) (1.1 g, 5.29 mmol)) and 4,5-dichloro-3-nitropyridin-2-amine (1 g, 4.81 mmol) were taken in IPA (30 ml) and DIPEA (4.6 ml, 26.44 mmol)) was added to the reaction mixture which was then heated at 60° C. for 24 h when TLC confirmed completion of reaction. The reaction mixture was cooled to rt and concentrated in vacuuo. Pure product (9) (1.63 g, 92%) was obtained as a yellow solid after purification by column chromatography using silica gel (100-200 mesh). NMR: δ (1H, 400 MHz, CDCl3): 0.87 (3H, s), 0.97 (3H, s), 1.05 (3H, s), 1.44-1.54 (1H, m), 1.70-1.80 (1H, m), 1.90-2.20 (1H, m), 2.30-2.40 (1H, m), 2.47 (1H, dd, J=3.2, 18.0 Hz), 2.88 (1H, d, J=18.4 Hz), 6.55 (2H, s), 7.85 (1H, s), 7.96 (1H, s) LCMS: (254 nm): [M+H]+ 339.10 (86.27%)
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:18]([CH3:24])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Yield: 92 %

Procedure:
Analogously to example 1 (f), the reaction of 684 mg of 4-[5-(4-chlorobenzyl)-7-isobutyloxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenol with tert-butyl bromoacetate gave 800 mg (92%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.C(N(C(C)C)C(C)C)C.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1.CO>O1CCCC1>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:34]([CH:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)=[O:35])[S:3][C:4]=2[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C3CCOCC3)nc12
Temperature: 0 °C
Yield: 94.1 %

Procedure:
To a solution of 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.4 mmol) in tetrahydrofurane (2 ml) were subsequently added N-ethyl-diisopropylamine (194 □1, 1.1 mmol) and tetrahydropyran-4-carbonyl chloride (77 mg, 0.52 mmol, dissolved in 0.5 ml tetrahydrofurane) and the mixture refluxed for 3 h. The mixture was then cooled to 0° C., methanol (0.4 ml) was added and the mixture slowly warmed to 20° C. Then the mixture was evaporated to dryness, dichloromethane was added (3 ml) and extracted with saturated aqueous sodium carbonate. After back extraction of the aqueous phase with two portions of dichloromethane (3 ml), the combined organic phases were dryed with Na2SO4 and the solvent evaporated. The crude product was was then chromatographed over SiO2, eluting with CH2Cl2/MeOH 98:2, the product fractions were pooled and the solvent evaporated, to afford the title compound as a beige powder (142 mg, 76% yield), MS: m/e=378(M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9].C(N(CC)CC)C>ClCCl>[C:7]([O:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])(=[O:10])[CH:8]=[CH2:9]
Reactant: CC(C)CCO
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3-methyl butanol (2.0 g, 22.6 mmol) and acryloyl chloride (2.05 g, 22.6 mmol) in dichloromethane (5 ml) at 0° C. is added dropwise triethylamine (3.2 ml, 22.7 mmol). The solution is stirred for 30 minutes at room temperature and then concentrated to a residue. The residue is washed with hexanes (2×10 ml) and the resultant combined organics are concentrated and filtered through a plug of silica to give 3.0 g of 3-methylbutyl acrylate as an oil, 93% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][N:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO.[Cl-].[Na+].O>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][N:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1ccc(C=NOCCCOc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(C=NOCCCOc2ccc(CO)cc2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-formyl-phenoxy)-propyl]-oxime (1.303 g, 3.84 mmol) in methanol (30 mL) was added sodium borohydride (0.201 g, 5.31 mmol) and the reaction was allowed to stir for 20 minutes. It was then poured slowly into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4-tert-butyl-benzaldehyde O-[3-(4-hydroxymethyl-phenoxy)-propyl]-oxime which was used without further purification. To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-hydroxymethyl-phenoxy)-propyl]-oxime in methylene chloride (30 mL) was added phosphorus tribromide (0.400 mL, 4.25 mmol) and the reaction was stirred at room temperature for 30 minutes. It was then poured slowly over ice and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4-tert-butyl-benzaldehyde O-[3-(4-bromomethyl-phenoxy)-propyl]-oxime (˜0.8 g) which was used without further purification. To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-bromomethyl-phenoxy)-propyl]-oxime (−0.8 g) in tetrahydrofuran (25 mL) was added tetrabutylammonium cyanide (0.650 g, 2.42 mmol) and the reaction was allowed to stir at room temperature overnight. It was then poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (10/90 to 15/85) to give {4-[3-(4-tert-butyl-benzylideneaminooxy)-propoxy]-phenyl}-acetonitrile (0.607 g, 45% over 3 steps) as a colorless oil. 1H NMR (300 MHz, CDCl3); δ 8.08 (s, 1H), 7.52 (d, 2H), 7.40 (d, 2H), 7.22 (d, 2H), 6.92 (d, 2H), 4.35 (t, 2H), 4.10 (t, 2H), 3.68 (s, 2H), 2.21 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:26])=[C:16]([F:25])[C:17]=2[C:19]#[C:20][Si](C)(C)C)[C:12](=[O:27])[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:10]1.[F-].[K+].O.CN(C)C=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:26])=[C:16]([F:25])[C:17]=2[C:19]#[CH:20])[C:12](=[O:27])[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Agent: [F-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(-c3ccc(F)cc3F)c12
Temperature: 20 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 4.6 g of ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate in 20 ml of chloroform is added dropwise at room temperature to a solution of 2 g of potassium fluoride in a solvent mixture of 3 ml of water, 25 ml of chloroform and 50 ml of dimethylformamide. The mixture is stirred for 1 hour at approx. 20° C., the reaction mixture is then treated with more chloroform and extracted several times by shaking with water, and the organic phase is dried and concentrated. The residue obtained is recrystallised from methanol. 3.4 g of ethyl 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are obtained (87% of theory).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[C:33]([NH:40][C@@H:41]2[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]2[N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH:32]=1.[NH2:53][C:54]1[CH:63]=[C:62]2[C:57]([CH2:58][CH2:59][C:60](=[O:65])[N:61]2[CH3:64])=[CH:56][CH:55]=1>O>[ClH:30].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:53][C:54]2[CH:63]=[C:62]3[C:57]([CH2:58][CH2:59][C:60](=[O:65])[N:61]3[CH3:64])=[CH:56][CH:55]=2)=[O:36])=[C:33]([NH:40][C@@H:41]2[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]2[N:47]2[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]2)[CH:32]=1
Reactant: O=C(O)c1ccc(Cl)cc1N[C@@H]1CCCC[C@H]1N1CCCCC1
Reactant: CN1C(=O)CCc2ccc(N)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3N[C@@H]3CCCC[C@H]3N3CCCCC3)cc21
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 114.1 %

Procedure:
HATU (406 mg) was added to a DMF solution of 4-chloro-2-{[(1R,2R)-2-piperidin-1-ylcyclohexyl]amino}benzoic acid (300 mg) and 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (173 mg), followed by stirring at room temperature for 24 hours. After adding water to the reaction liquid and extracting with ethyl acetate, the organic layer was dried with sodium sulfate, and then the solution was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 2:1). By treating the resulting free base with 4 M hydrogen chloride/ethyl acetate, 4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-{[(1R,2R)-2-piperidin-1-ylcyclohexyl]amino}benzamide hydrochloride (270 mg) was obtained as an amorphous.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1cccnc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCc1ccccc1)c1cccnc1F
Reaction time: 16 h
Yield: 14.3 %

Procedure:
2-Fluoro-nicotinic acid (0.793 g, 5.59 mmol) and phenethylamine (0.705 mL, 5.59 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (1.56 mL, 11.2 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.97 g, 7.83 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-40% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.196 g, 0.802 mmol, 14.3%). ESI-MS m/z calc. 244.1, found 245.2 (M+1)+. Retention time of 2.76 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH2:12][C:13]#[CH:14])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]#[C:27][C:28](O)=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(Cl)CCl.Cl.CN(C)CCCN=C=NCC>CO>[NH2:8][C:7]1[N:6]([CH2:9][CH3:10])[C:5](=[O:11])[N:4]([CH2:12][C:13]#[CH:14])[C:3](=[O:15])[C:2]=1[NH:1][C:28](=[O:29])[C:27]#[C:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1ccc(C#CC(=O)O)cc1OC
Reactant: C#CCn1c(=O)c(N)c(N)n(CC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: CO
Product: C#CCn1c(=O)c(NC(=O)C#Cc2ccc(OC)c(OC)c2)c(N)n(CC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the 5,6-diamino-1-ethyl-3-propargyluracil (4.2 g, 20 mmol), 3,4-dimethoxyphenylacetylencarboxylic acid (4.2 g, 20 mmol) and EDC ((1-(3-dimethylaminopropyl)-3-ethyl-carbodiimid hydrochloride; 4.2 g, 22 mmol) in methanol (100 ml) was stirred at room temperature for 2 h. The colorless product was precipitated by adding water (ca. 150 ml), filtered under reduced pressure, washed thoroughly with ether (TLC-control indicated the purity of the product; eluent: dichloromethane/methanol 9:1) and dried at 60° C. Yield: 6 g (76%).
Reaction SMILES: C([O:4][CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:8]=2[N:7]2[N:24]=[C:25]([C:27]([NH2:29])=[O:28])[N:26]=[C:6]12)(=O)C.CO.[OH-].[Na+].Cl>O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:9]2[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:8]=2[N:7]2[N:24]=[C:25]([C:27]([NH2:29])=[O:28])[N:26]=[C:6]2[CH:5]([OH:4])[N:11]=1
Reactant: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(OC(C)=O)N=C2c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(O)N=C2c1ccccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 0.86 g. of 4-acetoxy-6-(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]-diazepine-2-carboxamide in 5 ml. of methanol is added dropwise 2 ml. of a 1N-aqueous sodium hydroxide solution with stirring and ice-cooling. After 5 minutes, to the resulting mixture is added 2 ml. of a 1N-aqueous hydrochloric acid solution and then water. The resulting precipitate is collected by filtration and then washed with water to give 6-(2-chlorophenyl)-8-ethyl-4-hydroxy-4H-thieno[3,2-f]-s-triazolo[1,5-a]-[1,4]diazepine-2-carboxamide as crystals. Recrystallization from ethanol gives colorless prisms melting at 228° to 231° C.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>ClCCl>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([Cl:21])=[O:12])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCN(C2CC2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCN(C2CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 1-cyclopropyl piperidine-4-carboxylic acid (10.0 grams, 48.6 mmol, obtained in above step) in dichloromethane (198 mL) cooled at 0° C. was added dry dimethyl formamide (2 mL) followed by drop wise addition of oxalyl chloride (12.5 mL, 145.8 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The volatiles were removed under reduced pressure and the crude 1-cyclopropyl piperidine-4-carbonyl chloride (11.0 grams). This crude product was used in the next reaction without purification.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(#N)C.[Br:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[Br-:13].[CH2:14]([C:1]1[NH+:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: c1ccn2cncc2c1
Solvent: CCOCC
Solvent: CC#N
Product: [Br-]
Product: c1ccc(Cc2[nH+]cn3ccccc23)cc1

Procedure:
Imidazo[1,5-a]pyridine (3.9 g.) in 100 ml. of dry acetonitrile is treated with 6.8 g. of α-bromotoluene, and the resulting reaction mixture heated under reflux for 3 hrs. The solution is cooled and diluted with 250 ml. of diethyl ether. The resulting precipitate is filtered and recrystallized from isopropanol-diethyl ether, 7.92 g., m.p. 172°-176° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.C1COCC1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCOC(C)=O>[CH3:1][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)[C:6]=2[CH:10]=1
Reactant: Cc1cc2[nH]cnc2cc1C#N
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C#N)ncn2C1CCCCO1
Temperature: 75 °C
Yield: 59.7 %

Procedure:
To a stirred solution of 6-methyl-1H-benzo[d]imidazole-5-carbonitrile (7.9 g, 50 mmol, CASRN 952511-47-6) and THF (85 mL) at RT under nitrogen was added 3,4-dihydro-2H-pyran (34 g, 0.4 mol) and p-TsOH.H2O (0.9 g, 5 mmol) and the resulting mixture was heated at 75° C. for 3 h. The reaction mixture was cooled to RT, diluted with EtOAc (200 mL), and washed sequentially with sat'd. aq. Na2CO3 (300 mL) and brine (300 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 5% MeOH) to afford 7.2 g (60%) of 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (176) as a yellow oil: MS (ESI) m/z=242 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:19])[NH:14]C(C)(C)C)=[S:11].Cl>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:19])[NH2:14])=[S:11]
Reactant: Cc1cccc(C)c1NC(=S)NC(=O)NC(C)(C)C
Agent: Cl
Product: Cc1cccc(C)c1NC(=S)NC(N)=O

Procedure:
A mixture of 25.6 g. (0.1 mole) of 1-(2,6-dimethylphenyl)-3-(t-butylcarbamyl)thiourea and 200 ml. of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, the solid filtered and washed with 10 ml. of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanol-ether to obtain 1-(2,6-dimethylphenyl)-3-carbamylthiourea.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:27]([N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:31]1=[O:35])(=[O:29])[CH3:28]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)nc1C
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4nc(C)c(C)cc4C)CC3)c(C#N)c2)C1=O
Yield: 82.5 %

Procedure:
Using 5-bromo-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.24 g) described in Preparation Example 172 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.14 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].O.[NH2:10][NH2:11]>C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[N:10][NH2:11])[NH2:2]
Reactant: NN
Reactant: N#Cc1ccccn1
Solvent: CCO
Solvent: O
Product: NN=C(N)c1ccccn1
Reaction time: 8 h

Procedure:
2-Cyanopyridine (5.2 g, 50 mmol) and hydrazine hydrate (2.95 g, 50 mmol) were mixed and a small amount of ethanol was added to obtain a clear solution. After standing overnight at ambient temperature, the resulting white crystals were collected by filtration. The resulting product was washed with diethyl ether and dried in the air to afford pyridine-2-carbohydrazonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=1.[N:15]([O-:17])=[O:16].[Na+]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:3]=1
Reactant: Cc1cc(C)nc(N2CCOCC2)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCOCC2)nc(C)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
To 4-(4,6-dimethyl-pyridin-2-yl)-morpholine (9.4 g) dissolved in trifluoroacetic acid (250 mL) cooled to 0° C. was added sodium nitrite (3.54 g) over 15 minutes and the reaction mixture was then stirred 15 minutes at 0° C. The reaction mixture was concentrated in vacuo to app. 100 mL and the pH adjusted to 11 with concentrated aqueous sodium hydroxide (150 mL). Brine (200 mL) was added and the mixture was extracted with diethyl ether (4×150 mL), the organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was subjected to flash chromatography (SiO2, heptane/ethylacetate 4:1) to furnish 2.01 g (17% yield) of the title compound as a yellow solid. GC-MS (m/z) 237 (M+); tR=7.69. 1H NMR (500 MHz, DMSO-d6): 2.28 (s, 3H), 2.39 (s, 3H), 3.60 (m, 4H), 3.67 (m, 4H), 6.72 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)(O)[CH2:16][CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN(C=O)C.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6](/[CH:14]=[C:15](\[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)/[CH2:16][CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCC(O)(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)butan-2-ol (0.5 g, 1.43 mmol) was dissolved in dry DCM (15 mL) and a drop of DMF was added. The solution was cooled to 0° C. and thionyl chloride (0.5 g, 4.29 mmol) diluted with dry DCM (2 mL) was added dropwise. Stirring was continued for 1 h at 0° C. and then at RT for 2 h. The solution was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. 1H NMR (CDCl3, freebase) δ (ppm): 8.36 (d, 2H), 7.16 (s, 1H), 7.0 (d, 1H), 6.90 (d, 1H), 6.85 (d, 2H), 6.75 (s, 1H), 3.70 (s, 2H), 2.78 (t, 2H), 2.65 (q, 2H), 2.50 (s, 3H), 2.42 (m, 2H), 2.40 (s, 3H), 1.18 (t, 3H).