Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1([F:15])[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1.[CH3:16][N:17](C=O)[CH3:18].N(C)C>C(Cl)Cl.C1COCC1>[F:7][C:8]1([F:15])[CH2:11][CH:10]([C:12]([N:17]([CH3:18])[CH3:16])=[O:13])[CH2:9]1
Reactant: CN(C)C=O
Reactant: O=C(O)C1CC(F)(F)C1
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Oxalyl chloride (21.74 mL, 248 mmol) was added dropwise to a stirred solution of 3,3-difluorocyclobutanecarboxylic acid (26 g, 191 mmol; prepared as described in Syn. Comm., 35:657 (2005) (Elend, D. et al.) in CH2Cl2 (500 mL) and DMF (0.5 mL) at 0° C. The reaction mixture was allowed to come to RT and stirred at RT for 1 h prior to being concentrated at RT using a rotary evaporator at ca. 50 mm Hg vacuum. After adding THF (300 mL) to the resulting residue, the stirred solution was cooled 0° C. prior to addition of a 2M solution of Me2NH (478 mL, 955 mmol) in THF. After stirring the reaction mixture at RT for 0.5 h, the mixture was partitioned between ether and 5% aq. Na2CO3. The organic layer was dried over MgSO4 and concentrated in vacuo at RT. After portioning the residue between CH2Cl2 and water, the organic layer was dried over MgSO4 and concentrated in vacuo at RT to give 3,3-difluoro-N,N-dimethylcyclobutanecarboxamide (24 g, 147 mmol, 77% yield) as a brown semi solid, used as such in the next step. 1H NMR (400 MHz, CDCl3) δ 2.82-3.13 (9H, m), 2.62-2.79 (2H, m).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]=1)=O.Cl.[NH2:14]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]=1)#[N:14]
Reactant: NO
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
A mixture of 3-formyl-5-methylindole (0.50 g), hydroxylamine hydrochloride (0.44 g) and sodium acetate (0.52 g) in acetic acid (5 ml) was stirred for 2 hours, then acetic anhydride (2.5 ml) was added to the mixture and allowed to react under reflux for 0.5 hour. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate. After filtration of insoluble materials, the filtrate was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and chloroform. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give 3-cyano-5-methylindole (109 mg).
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][CH:29]1[C:34](=O)[CH2:33][CH2:32][O:31][CH2:30]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:34]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentanamine (80 mg, 0.2 mmol), 3-methyltetrahydro-4H-pyran-4-one (71 mg, 0.62 mmol) and triethylamine (0.12 mL, 0.83 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (130 mg, 0.62 mmol). After being stirred at room temperature overnight, the solution was diluted with dichloromethane. The resulting solution was washed with NaHCO3 and brine, dried over MgSO4 and concentrated. The residue was purified on silica gel to give the desired product which was further separated by chiral HPLC affording four isomers. MS calculated for C26H38F3N3O2: (M+H) 482; found 482.2 for four isomers.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=1)=[O:7].[CH2:28]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:2][C:3]2[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=2)[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:36][CH:37]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)Cc1ccc(O)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(CCl)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(COc3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 50 °C
Yield: 84.8 %

Procedure:
A mixture of ethyl 4-[3-[3-(chloromethyl)benzoyl]indol-1-yl]butyrate (42.5 mg) and 4-isobutylphenol (18.3 mg) and potassium carbonate (30.6 mg) in N,N-dimethylformamide (3 ml) was heated at 100° C. for 1 hour and 50° C. for 10 hours. The mixture was worked up in an usual manner and purified by thin layer silica gel chromatography eluting with a mixture of ethyl acetate and hexane (1:2) to give ethyl 4-[3-[3-(4-isobutylphenoxymethyl)benzoyl]indol-1-yl]butyrate (46.7 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(C(F)(F)F)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-(trifluoromethyl)-benzenesulfonyl chloride. Purity (ELSD, based on MW=629.6)=97%.
Reaction SMILES: [Br-:1].[OH:2][C:3]([C:30]1[CH:35]=[CH:34][C:33](OC)=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:4]([O:6][C@@H:7]1[CH:12]2[CH2:13][CH2:14][N+:9]([CH2:15][C:16](=[O:23])[NH:17][C:18]3[CH:22]=[CH:21][O:20][N:19]=3)([CH2:10][CH2:11]2)[CH2:8]1)=[O:5].N12CCC(CC1)[C@@H](OC(=O)C(O)(C1C=CC(OC)=CC=1)C1C=CC=CC=1)[CH2:39]2.N12CCC(CC1)[C@@H](OC(=O)C(O)(C1C=CC=CC=1)C1C=CC=CC=1C)C2>>[Br-:1].[OH:2][C:3]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:39])[C:4]([O:6][C@@H:7]1[CH:12]2[CH2:11][CH2:10][N+:9]([CH2:15][C:16](=[O:23])[NH:17][C:18]3[CH:22]=[CH:21][O:20][N:19]=3)([CH2:14][CH2:13]2)[CH2:8]1)=[O:5]
Reactant: COc1ccc(C(O)(C(=O)O[C@H]2C[N+]3(CC(=O)Nc4ccon4)CCC2CC3)c2ccccc2)cc1
Reactant: COc1ccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Agent: Cc1ccccc1C(O)(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: [Br-]
Product: Cc1ccccc1C(O)(C(=O)O[C@H]1C[N+]2(CC(=O)Nc3ccon3)CCC1CC2)c1ccccc1

Procedure:
This compound is prepared using an method analogous to (R)-3-[2-hydroxy-2-(4-methoxy-phenyl)-2-phenyl-acetoxy]-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]-octane bromide (Example 22) by replacing hydroxy-(4-methoxy-phenyl)-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Intermediate O) with hydroxy-phenyl-o-tolyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Intermediate P).
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)C(O)CCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(CCCCc1ccccc1)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Methyl 3-hydroxy-2,2-dimethyl-7-phenylheptanoate (10 g, 38 mmol) and triethylamine (6.3 mL, 45 mmol) are dissolved in CH2Cl2 (50 mL) and cooled to 0° C. Methanesulfonyl chloride (3.2 mL, 42 mmol) is added and the reaction is allowed to stir at room temperature for 1 hour. The reaction mixture is then washed with NaHCO3 (2×40 mL), 1 N HCl (40 mL) and brine (40 mL). The solution is dried over MgSO4 and the solvent removed in vacuo to yield methyl 3-methanesulfonyloxy-2,2-dimethyl-7-phenylheptanoate (11.2 g, 86%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.19-7.15 (m, 3H), 4.99 (dd, J=9.2, 2.0 Hz,1H), 3.69 (s, 3H), 2.93 (s, 3H), 2.62 (t, J=7.4 Hz, 2H), 1.71-1.38 (m, 6H), 1.27 (s, 3H), 1.18 (s, 3H); MS (FAB) m/e 343 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])=[CH:26][CH:25]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2c(C)c([N+](=O)[O-])cc3nc(OC)c(OC)nc23)cc1
Reaction time: 16 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and 4-methoxybenzylamine 0.11 mL (0.84 mmol). Reaction was continued for 16 hours, and the crude product was recrystallized from hexanes:ethyl acetate to give yellow needles, 156 mg (47%), mp 187-189° C.; 1H NMR (CDCl3): δ 8.32 (s, 1H, 8-H), 7.28 (d, 2H, J=8.5 Hz), 6.85 (d, 2H, J=8.5 Hz), 6.07 (bs, 1H), 4.61 (d, 2H, J=5.6 Hz), 4.05 (s, 3H), 3.97 (s, 3H), 3.76 (s, 3H), 2.56 (s, 3H); MS (APCI): m/z 413 (M+1). Anal. Calcd. for C20H20N4O6: C, 58.25; H, 4.89; N, 13.59. Found: C, 58.55; H, 4.85; N, 13.47.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CN(C)C=O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: C1COCCN1
Reactant: Clc1nccnc1Cl
Solvent: CN(C)C=O
Product: Clc1nccnc1N1CCOCC1

Procedure:
A mixture of 2,3-dichloropyrazine (5 g., 0.034 mmole), morpholine (5.8 g., 0.067 mmole), and 50 ml. of dimethylformamide are heatd at 90°-120° C. for 6-14 hours, in an atmosphere of nitrogen. The reaction mixture is cooled and evaporated to dryness at a water-bath temperature of 55° C. A chloroform solution of the residue is extracted twice with 0.1 M sodium hydroxide, dried over magnesium sulfate and evaporated to leave the product.
Reaction SMILES: [C:1](=[O:34])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:15][C:6]2[C:7]3[CH:8]=[N:9][NH:10][C:11]=3[C:12]([Cl:14])=[CH:13][C:5]=2[CH2:4]1.CN(C=O)C.C(N(CC)CC)C.[NH:47]1[CH2:52][CH2:51][CH:50]([N:53]2[C:61]3[C:56](=[N:57][CH:58]=[CH:59][CH:60]=3)[NH:55][C:54]2=[O:62])[CH2:49][CH2:48]1>>[O:62]=[C:54]1[NH:55][C:56]2=[N:57][CH:58]=[CH:59][CH:60]=[C:61]2[N:53]1[CH:50]1[CH2:51][CH2:52][N:47]([C:1]([O:2][C@H:3]2[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:21])[F:22])[CH2:15][C:6]3[C:7]4[CH:8]=[N:9][NH:10][C:11]=4[C:12]([Cl:14])=[CH:13][C:5]=3[CH2:4]2)=[O:34])[CH2:48][CH2:49]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 12 h
Yield: 80 %

Procedure:
(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-nitrophenyl carbonate (115 mg, 0.23 mmol) in DMF (10.00 mL, 129 mmol) was added triethylamine (0.128 mL, 0.920 mmol) followed by 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one, 1.00HCl (70.3 mg, 0.276 mmol). After 12 h, the solvent was removed and the product was purified by flash chromatography using 5% methanol in dichloromethane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (106 mg, 0.183 mmol, 80% yield). 1H NMR (500 MHz, CD3OD): in δ 8.29 (s, 1H), 8.03 (br, 1H), 7.96 (d, J=5.5 Hz, 1H), 7.71 (m, 1H), 7.27 (s, 1H), 7.13-7.12 (m, 1H), 6.10 (m, 1H), 5.44 (d, J=17 Hz, 1H), 4.88 (d, J=17 Hz, 1H), 4.72-4.60 (m, 2H), 4.50-4.39 (m, 1H), 4.38-4.22 (m, 1H), 4.21-4.02 (m, 1H), 3.40-3.40 (m, 1H), 3.39-3.27 (m, 2H), 3.23-2.97 (m, 2H), 2.71-2.23 (m, 2H), 1.95-1.74 (m, 2H); MS (ESI) 578 (M+H); Rf=2.15.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:65]1([C:71](=[O:79])[CH2:72][N:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[CH:9]([C:28]([N:76]3[CH2:77][CH2:78][N:73]([CH2:72][C:71]([N:65]4[CH2:66][CH2:67][O:68][CH2:69][CH2:70]4)=[O:79])[CH2:74][CH2:75]3)=[O:30])[NH:10][CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (5 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA (0.145 mL, 0.83 mmol) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood, 44 mg, 0.21 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12 g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 63 mg.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][N:30]([CH2:41][CH2:42][OH:43])[S:31]([C:34]1[S:35][C:36]([Cl:40])=[C:37]([NH2:39])[CH:38]=1)(=[O:33])=[O:32]>>[OH:27][CH2:28][CH2:29][N:30]([CH2:41][CH2:42][OH:43])[S:31]([C:34]1[S:35][C:36]([Cl:40])=[C:37]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:38]=1)(=[O:32])=[O:33]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cc(S(=O)(=O)N(CCO)CCO)sc1Cl
Product: O=C(Nc1cc(S(=O)(=O)N(CCO)CCO)sc1Cl)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.5) according to general procedure II.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1.CCCCCC>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH:10]=[C:6]([CH2:4][OH:3])[CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CO)C1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 5.43 g (22.5 mmol) 2,5-dihydro-pyrrole-1,3-dicarboxylic acid 1-tert.-butylester 3-ethyl ester in 50 ml THF, cooled to −78° C. was dropwise added 50 ml of a 1N DIBAL-H solution in hexane. The mixture was allowed to warm to room temperature overnight. As TLC analysis indicated complete consumption of starting material, the mixture was cooled in an ice bath and 1.90 g water were cautiously added, followed by 1.90 g 15% aqueous NaOH and 5.70 g water. The white precipitate was filtered off, washed thoroughly with ether and the combined filtrates were evaporated. Bulb-to-bulb distillation of the residual pale yellow oil gave 4.13 g (93%) 3-hydroxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester as a colorless oil, b.p. 130° C. (0.2 mbar).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[Cl:24]Cl.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[C:23]=1[Cl:24]
Reactant: ClCl
Reactant: CCC1N=C(c2ccccc2F)c2cc(N)ccc2N(C)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC1N=C(c2ccccc2F)c2c(ccc(N)c2Cl)N(C)C1=O

Procedure:
13 g (0.042 M) of rac-7-amino-3-ethyl-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are dissolved in 70 ml of concentrated hydrochloric acid at -10° C. and chlorine gas is then conducted in at -10° C. until the starting material can no longer be detected by thin-layer chromatography. The mixture is neutralised slowly with a mixture of ice and 10% sodium carbonate solution and the mixture is extracted several times with methylene chloride. The organic solution is washed with water, dried over sodium sulphate, filtered and concentrated. The residue is purified on a 300 g silica gel column with methylene chloride/ethyl acetate (10:1) and crystallised from ethanol. There is obtained rac-7-amino-3-ethyl-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one which melts at 250° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]([O:21][CH3:22])[CH:6]1[CH2:10][S:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[N:7]1.[CH3:23][N:24](C=O)[CH3:25]>>[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][O:4][CH:5]([O:21][CH3:22])[CH:6]1[CH2:10][S:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[N:7]1
Reactant: COC(OCCBr)C1CSC(c2nc3ccc(O)cc3s2)=N1
Reactant: CN(C)C=O
Product: COC(OCCN(C)C)C1CSC(c2nc3ccc(O)cc3s2)=N1
Reaction time: 28 h

Procedure:
To a vial containing 2-(4-((2-bromoethoxy)(methoxy)methyl)-4,5-dihydrothiazol-2-yl)benzo[d]thiazol-6-ol (16 mg) in DMF (200 uL) dimethylamine (40 uL of 2M in THF) was added. After 28 hours at room temperature, the reaction was purified by preparative RP-HPLC to yield 8 mg. 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=9.2, 1H), 7.14 (d, J=2.2, 1H), 6.97 (d, J=8.9, 1H), 4.74-4.59 (m, 2H), 4.12-3.78 (m, 1H), 3.21 (dd, J=7.2, 14.9, 1H), 3.10 (s, 2H), 2.63 (s, 5H), 1.29 (t, J=7.3, 1H). mass (MH+) calc and found 368.
Reaction SMILES: O=S(Cl)Cl.[CH3:5]O.[OH:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12]>C(OCC)(=O)C>[OH:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([O:13][CH3:5])=[O:12]
Reactant: CO
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100 %

Procedure:
SOCl2 (0.6 mL) was added dropwise to anhydrous MeOH (10 mL) at 0° C. The mixture was stirred at this temperature for 0.5 h, then 3-hydroxy-2-nitrobenzoic acid (0.6 g, 3.2 mmol) was added to the mixture. The resulting mixture was heated at reflux for 4 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The resulting mixture was concentrated in vacuo to give the title compound (0.63 g 100%) as a brown solid.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(CC)C(C)C)(C)C.[N:14]([CH2:17][CH:18]([S:32][S:33][CH3:34])[CH2:19][C@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([OH:23])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[C:3]([CH2:2][O:23][C:21](=[O:22])[C@@H:20]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:19][CH:18]([S:32][S:33][CH3:34])[CH2:17][N:14]=[N+:15]=[N-:16])#[N:4]
Reactant: N#CCBr
Reactant: CSSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
Bromoacetonitrile (45 μl, 0.669 mmol) and N,N-diisopropylethylamine (58 μl, 0.334 mmol) were added to a solution of (S)-5-azido-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid (Compound 35) (75 mg, 0.223 mmol) in acetonitrile (2 ml), and the reaction solution was stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate/saturated ammonium chloride, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-5-azido-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid cyanomethyl ester (Compound 36) (81 mg, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37](=[CH2:41])[CH2:38][CH2:39]O.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:39][CH2:38][C:37]([CH3:41])=[CH2:36])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C=C(C)CCO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Product: C=C(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 3-methyl-3-butene-1-ol in place of isobutanol (yield: 0.1327 g, 91%). mp 109–111° C. 1H NMR (300 MHz, DMSO d6) δ 1.61 (s, 3H), 2.32 (t, J=7 Hz, 2H), 3.30 (s, 3H), 4.56 (t, J=7 Hz, 2H), 4.63 (bs, 1H), 4.68 (bs, 1H), 7.37 (m, 2H), 7.66 (m, 2H), 7.90 (m, 2H), 8.05 (m, 2H), 8.19 (s, 1H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal. calc. for C22H21FN2O4S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.50; H, 5.00; N, 6.45.