Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29](C)=[O:30])=[C:24]([CH3:32])[CH:23]=1>CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:29]([C:25]4[C:24]([CH3:32])=[CH:23][C:22]([CH3:21])=[CH:27][C:26]=4[CH3:28])=[O:30])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(C)cc(C)cc1C
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3C(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
To a solution of 8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (32.9 mg, 0.125 mmol) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (19.8 μL, 0.142 mmol) at 0° C. After 15 min, to the mixture was added 2,4,6-trimethylacetophenone (27.2 mg, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 hrs. The mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed and brine (×1), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from n-hexane to give the title compound as a pale pink powder (24.0 mg, 0.0585 mmol, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:30][NH:31][O:32][CH3:33].CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[CH3:4][C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:31]([CH3:30])[O:32][CH3:33])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])[CH3:3]
Reactant: CNOC
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-leucine (3.00 g, 13.0 mmol) in THF (25.0 mL) was added 1,1′-carbonyldiimidazole (2.52 g, 15.6 mmol) portionwise over about 10 min. After stirring 1 h at RT, a solution of N,O-dimethylhydroxylamine hydrochloride (1.39 g, 14.3 mmol) and DIPEA (2.49 mL, 14.3 mmol) in DMF (6.0 mL) was added. The reaction mixture was stirred for 2.5 h at RT, followed by concentration in vacuo. The residue was diluted with EtOAc (50 mL) and washed with 1 M aq. HCl (2×20 mL), saturated aq. NaHCO3 (2×20 mL), and brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (2.34 g, 66%) as a clear, colorless oil. LC-MS m/z 275 (M+H)+, 1.17 min (ret time).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COc1cccc(N)c1OC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1cccc(OC)c1OC)C(=O)OCC
Temperature: 80 °C
Yield: 90.1 %

Procedure:
To a mixture of 2,3-dimethoxyaniline (20 g, 131 mmol) in Ethanol (50 mL) was added diethyl 2-(ethoxymethylene)malonate (26.2 mL, 131 mmol). The mixture was heated at 80° C. for 1 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo to remove ethanol, and washed with hexane to afford diethyl 2-(((2,3-dimethoxyphenyl)amino)methylene)malonate (38 g, 118 mmol, 90% yield) as a white solid. This crude mixture was directly used in next step. LCMS: (M+H)+: 324.2.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[C:5]([Cl:11])=[CH:4][C:3]=1[Cl:12].Br[C:14]1[C:22]2[N:21]=N[NH:19][C:18]=2C(Cl)=C(Br)C=1Cl.Cl[C:27]1C=C(Cl)C2NN=NC=2C=1>>[NH2:21][C:22]([CH3:14])([CH2:27][N:8]1[N:7]=[C:6]2[C:5]([Cl:11])=[CH:4][C:3]([Cl:12])=[C:2]([Br:1])[C:10]2=[N:9]1)[C:18]#[N:19]
Reactant: Clc1cc(Cl)c2[nH]nnc2c1Br
Reactant: Clc1c(Br)c(Cl)c2[nH]nnc2c1Br
Reactant: Clc1cc(Cl)c2[nH]nnc2c1
Product: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Br)c2n1

Procedure:
2-Amino-3-(4-bromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile was prepared using a procedure similar to that described in Example 1, part a and b, except starting from 4-bromo-5,7-dichloro-1H-benzotriazole that was prepared along with 4,6-dibromo-5,7-dichloro-1H-benzotriazole using a procedure similar to that described in Example 53 except using 5,7-dichloro-1H-benzotriazole described in Example 15.
Reaction SMILES: C(N1CC=C(C2C3C(=CC(C(N4CCN(C(C)C)CC4)=O)=CC=3)NC=2)CC1)C(C)C.Cl.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41]([OH:43])=[O:42])[CH:39]=2)[CH:34]=[CH:33]1.[CH2:44]([N:51]1[CH2:56][CH2:55][C:54](=O)[CH2:53][CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:44]([N:51]1[CH2:52][CH:53]=[C:54]([C:34]2[C:35]3[C:40](=[CH:39][C:38]([C:41]([OH:43])=[O:42])=[CH:37][CH:36]=3)[NH:32][CH:33]=2)[CH2:55][CH2:56]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CC(C)CN1CC=C(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: Cl
Product: O=C(O)c1ccc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c2c1

Procedure:
According to the procedure described for the synthesis of [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone; hydrochloride (Example 1; step 2) the title compound was prepared from indole-6-carboxylic acid (commercially available) and 1-benzyl-4-piperidone (commercially available). MS (m/e): 333.2 (MH+).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:15]([C:26]([O:28][CH2:29][CH2:30][C:31]#[N:32])=[O:27])=[C:14]([CH3:33])[NH:13][C:12]=1[CH3:34])=[O:10])C1C=CC=CC=1.C(O)=O.CO>C(Cl)(Cl)Cl.[Pd]>[C:31]([CH2:30][CH2:29][O:28][C:26]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:34])[NH:13][C:14]=1[CH3:33])=[O:27])#[N:32]
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(C)N1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CC1=C(C(=O)O)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
The solution of 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4- (4-nitrophenyl)pyridine (3.24 g, 7.02 mmol) in 160 ml of 4.4% (w/w) formic acid/MeOH mixture was stirred with Pd/C (10%, 3.24 g) for 30 min., the reaction was quenched by addition of 10 ml of CHCl3. The mixture was filtered and concentration of filtrate give a yellow powder, which was dissolved in CHCl3, washed with water and 1N HCL. After drying and removal of solvent, 3-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine-5-carboxylic acid was obtained as a yellow powder (1.94 g, 75%)
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10](Cl)=[O:11].[NH:14]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.Cl>O1CCCC1>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]([N:14]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:11]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CCOC(=O)C1CCCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)Cc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
223 g (1.125 mol) of mesityleneacetyl chloride are added dropwise at 0° to 10° C. to 182 ml (1.157 mol) of ethyl pipecolinate and 162 ml (1.157 mol) of triethylamine in 1,200 ml of absolute tetrahydrofuran (THF), followed by stirring for 1 hour at room temperature. After the mixture has been stirred into 5 liters of ice water and 500 ml of 1N HCl, the product is filtered off with suction, washed with water and dried in vacuo at 50° C. over P2O5. 342.3 g (95.2% of theory) of ethyl N-(2,4,6-trimethylphenylacetyl)-piperidine-2-carboxylate are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:8]2[O:9][C:10]([CH3:15])([CH3:14])[CH:11]3[O:13][CH:12]3[C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[NH3:21]>C(O)C>[C:1]([NH:4][C:5]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:8]2[O:9][C:10]([CH3:15])([CH3:14])[C@@H:11]([OH:13])[C@H:12]([NH2:21])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C1OC21
Solvent: CCO
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H](O)[C@@H]2N
Temperature: 25 °C
Reaction time: 120 h

Procedure:
6-Acetamido-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-benzo[b]pyran (1.0 g, the preparation of which is described in European Pat. No. 28,064) was dissolved in dry ethanol (150 ml) and saturated with ammonia during 3 h, with cooling. The reaction mixture was stirred at room temperature for 5 days and evaporated. The crude residue was purified on the chromatotron (80% ethyl acetate-pentane to 20% methanol-ethyl acetate gradient elution), to give the title compound (410 mgm). A small portion was converted to the hydrochloride salt and recrystallised from ethanol-diethyl ether, with m.p. 258°-261° C.
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH2:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][CH2:26][CH2:27]Br.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:27][CH2:26][CH2:25][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=2)[NH:21][CH:20]=1
Reactant: NCC1COc2ccccc2O1
Reactant: COc1ccc2[nH]cc(CCCBr)c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCCNCC3COc4ccccc4O3)c2c1
Temperature: 80 °C
Yield: 33.6 %

Procedure:
2,3-Dihydro-1,4-benzodioxin-2-methanamine hydrochloride (2.3 g, 11.0 mmole) in DMF (100 ml) was slowly added to a mixture of 5-methoxy-3-(3-bromopropyl)indole (3.0 g, 11.0 mmole) and diisopropylethylamine (9.7 ml, 55 mmole) in 100 ml of DMF with stirring and the mixture was heated at 80° C. for 24 hours. Most of DMF was removed in vacuum and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and chromatographed on silica gel using ethyl acetate as the eluant. The combined fractions of free base of the expected product (1.3 g, 3.7 mmole, 34%) were concentrated, treated with 0.25M of fumaric acid in ethanol (8.1 ml, 2.0 mmole) and diluted first with 50 ml of ethanol-diethyl ether (1:1) and then with a minimum amount of hexane to precipitate the title compound as a white solid, (2:1) fumarate salt, m.p. 135°-136° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][CH2:25][NH2:26]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:26][CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([CH3:20])[CH:29]=[CH:28][CH:27]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: Cc1cccc(CCN)c1
Product: Cc1cccc(CCNCc2ccc(Oc3ccc(C(N)=O)nc3)c(F)c2)c1
Yield: 52.4 %

Procedure:
Using a method similar to Example 405, using 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 405, Part B) (0.040 g, 0.154 mmol) and 3-methylphenethylamine (0.021 g, 0.154 mmol) gives the title compound (0.0306 g, 52.5%): TOF MS ES+ 380.2 (M+H)+, HRMS calcd for C21H23N3O2F 380.1774 (M+H)+, found 380.1757, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 m, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=8.4 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[H][H]>C(O)C.[Pt](=O)=O>[NH2:9][C:5]1[CH:4]=[C:3]([OH:12])[C:2]([Cl:1])=[CH:7][C:6]=1[F:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1cc(O)c(Cl)cc1F
Yield: 85.3 %

Procedure:
A suspension of 2-chloro-4-fluoro-5-nitrophenol (9.17 g) and platinum dioxide (500 mg) in ethanol (120 ml) was subjected to catalytic reduction with hydrogen at room temperature and atmospheric pressure until a designed amount of hydrogen was absorbed. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was extracted with ether, and the ether layer was concentrated to obtain 6.6 g of 3-amino-6-chloro-4-fluorophenol. M.P., 145°-146° C. (decomp.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(Oc2ccccc2)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1ccc(Oc2ccccc2)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-methoxy-5-phenoxyaniline (62 mg, 0.290 mmol) similar to Example 58 and isolated as a tan solid (46 mg, 54%). 1H NMR (CDCl3): 9.57 (dd, J=1.1, 2.3 Hz, 1H), 8.67 (dd, J=1.8, 4.8 Hz, 1H), 8.42–8.38 (m, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.38–7.31 (m, 2H), 7.25–7.21 (m, 1H), 7.11 (t, J=1.2 Hz, 1H), 7.09–7.03 (m, 2H), 6.91 (d, J=8.7 Hz, 2H), 6.82 (dd, J=2.7, 8.7 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:33][C:34]([CH3:36])=[O:35]>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:34]([CH3:36])([OH:35])[CH3:33])(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(C)(=O)=O)ccc2n1CC1CC1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-5-(methylsulfonyl)-1H-benzimidazole (Example 4, 67 mg, 0.21 mmol) in tetrahydrofuran was added lithium bis(trimethylsilyl)amide (1.06 M in hexane, 217 μL, 0.23 mmol) at −40° C. under nitrogen atmosphere. After stirring for 5 min, excess acetone was added at −40° C. and the mixture was allowed to warm to room temperature. After stirring for 18 h, the mixture was quenched with saturated ammonium chloride aqueous solution and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by PTLC (hexane:ethyl acetate=1:1, three times) to afford the title compound (6.4 mg, 8%) as a white amorphous solid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].FC(F)(F)C(O)=O.[NH2:13][C@H:14]1[CH2:17][O:16][C:15]1=[O:18].[OH-].[Na+]>O>[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:17][C@@H:14]([C:15]([OH:18])=[O:16])[NH2:13]
Reactant: N[C@H]1COC1=O
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCCSC[C@H](N)C(=O)O

Procedure:
To 2-aminoethanethiol hydrochloride (201 mg, 1.77 mmol) in degassed H2O (3.0 mL) was added (S)-3-amino-2-oxetanone trifluoroacetic acid salt (produced from BOC-L-serine β-lactone (151 mg, 0.807 mmol)) in H2O (1.0 mL). The pH of the stirred solution was maintained at 5.0-5.5 by dropwise addition of 1N NaOH. When additions of base were no longer required to maintain the pH at 5.5 (~35 min), the mixture was applied to a column of BioRad AG50-X8 (trademark) (80 mL, 3 cm dia., H+ form) and eluted with a linear gradient (0 to 0.2M over 1.0 L) of aqueous HC1 (2 mL/min). Lyophilization of the chromatographically pure fractions yielded 138 mg 85%) of S-(aminoethyl)-L-cysteine hydrochloride which was recrystallized from EtOH/acetone (85% recovery) for elemental analysis: mp 193°-194° C. (dec) (lit. mp 192°-192.5° C., 205°-207° C.); [α]D 25 +7.2 (c 1.0, H2O) (lit. [α]D +7.2 (c 1, H2O)); IR (KBr disk) 3650-2100 (s, br), 2000 (W, br), 1622 (s), 1587 (s), 1516 (s), 1494 (s), 1463 (s), 1427 (s), 1415 (s), 1400 (s), 1348 (s), 1303 (s), 560 (m) cm-1 ; 1H-NMR (300 MHz, D2O)δ 4.00 (dd, 1H, 4.8, 6.0 Hz, CH), 3.27 (t, 2H, 6.5 Hz, CH2NH3+), 3.16 (dd, 1H, 4.8, 14 Hz, CHCHHS), 3.14 (d, 6.0, 14 Hz, CHCHHS), 2.94 (t of d, 1H, 6.5, 14 Hz, SCHH), 2.92 (t of d, 1H, 6.5, 14.0 Hz, SCHH). Anal. Calc. for C5H13N2O2SCl: C, 29.92; H, 6.54; N, 13.96; Cl, 17.66; S, 15.97. Found: C, 29.59; H, 6.44; N, 13.98; Cl, 17.40; S, 15 88; POSFAB-MS (glycerol/HC1) 165 (MH+), 329 (M2H+); Rf~0.20 (System A).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C@H:11]([NH:13][C:14]2[C:15]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=4)[NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[NH:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C@@H:11]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH3:12])[C:15]=3[CH:22]=2)=[CH:28][CH:27]=1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CO)cc3)cc12)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CCl)cc3)cc12)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of thionyl chloride (25.7 ml, 0.328 mol) in 180 ml of toluene is cooled to −10° C. Solid {4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol (11.3 g, 0.0328 mol) is added in 8 portions over a range of 1 h. The temperature is then increased slowly to 0° C. and the mixture stirred for 2 h. The cold reaction mixture is filtered and the solid washed with toluene and ether. The crude product is suspended in water and treated with saturated sodium bicarbonate solution until the mixture turns basic. The mixture is stirred well for about 10 min and filtered. The solid is thoroughly washed with water and dried under reduced pressure to give the title compound; m.p. >320° C.; Rf (dichloromethane/ethanol 9:1)=0.46; HPLC tR=10.63 min; MS-ES+: (M+H)+=363.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][CH:49]1[CH2:55][CH2:54][S:53][CH:52]2[CH2:56][CH2:57][CH2:58][CH:59]([CH2:60][CH3:61])[N:51]2[C:50]1=[O:62]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9]([NH:48][C@H:49]1[CH2:55][CH2:54][S:53][C@H:52]2[CH2:56][CH2:57][CH2:58][C@@H:59]([CH2:60][CH3:61])[N:51]2[C:50]1=[O:62])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: CCC1CCCC2SCCC(N)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4OC)C3=O)Cc3ccccc3)C(=O)N12

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7R,10aS)-7-ethyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (36 mg, 0.067 mmol) and Intermediate 74 (23 mg, 0.067 mmol) to give a white solid (25 mg, 49% yield). Anal. Calcd. for C44H56N4O5S m/z 752.7. found: 753.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.07 (m, 11H), 7.07-6.87 (m, 3H), 5.24 (s, 1H), 5.00-4.84 (m, 1H), 4.81-4.69 (m, 1H), 4.38-4.26 (m, 1H), 4.09-3.83 (m, 1H), 3.79 (d, J=3.5 Hz, 3H), 3.47-3.27 (m, 1H), 3.22-3.03 (m, 1H), 2.90-2.54 (m, 5H), 2.45-2.28 (m, 2H), 2.23-1.94 (m, 11H), 1.93-1.76 (m, 3H), 1.77-1.59 (m, 4H), 1.50 (d, J=29.0 Hz, 3H), 1.39-1.22 (m, 1H), 0.97-0.82 (m, 3H).
Reaction SMILES: [CH2:1]([C:4]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl.[H-].[Na+]>CN(C=O)C>[CH2:1]([C:4]1([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[O:9][C:8](=[O:10])[N:7]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:19]=2[Cl:18])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccc(F)cc2)CCNC(=O)O1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(c2ccc(F)cc2)CCN(Cc2ccc(Cl)cc2Cl)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
To a stirred solution of 6-allyl-6-(4-fluorophenyl)-1,3-oxazinan-2-one (15 mg, 0.064 mmol) and 2,4-dichlorobenzyl chloride (25 mg, 0.13 mmol) in dry DMF (0.5 mL) under N2 was added 60% NaH in oil in small portions until gas evolution ceased. The mixture was stirred overnight at rt and quenched with water (0.5 mL). The mixture was applied to a 10-mL Chem-Elut cartridge and eluted with ether (50 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford 6-allyl-3-(2,4-dichlorobenzyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (5.5 mg, 22%). LC-MS Method 1 tR=2.1 min, m/z=394; 1H NMR (CDCl3) 2.30 (2H), 2.60 (m, 2H), 2.96 (m, 1H), 3.08 (m, 1H), 4.44 (d, 1H), 4.65 (d, 1H), 4.75 (1H), 5.06 (m, 2H), 5.67 (m, 1H), 6.86 (d, 1H), 7.08 (3H), 7.30 (3H).
Reaction SMILES: [CH3:1][I:2].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1>CC(C)=O>[I-:2].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([C:16]2[CH:17]=[N+:18]([CH3:1])[CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1
Reactant: CI
Reactant: COCCOCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: COCCOCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 9 mmol) and 3-(4-(2-(2-methoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone (10 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.76 g (60%).
Reaction SMILES: FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:26][C:27]1[C:37]2[N:36](C)[C:35](=[O:39])[C:34]([CH3:41])([CH3:40])[N:33]=[C:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[F:48])[C:31]=2[CH:30]=[C:29]([N+:49]([O-:51])=[O:50])[CH:28]=1>C(O)(C)C.C(Cl)Cl>[Cl:26][C:27]1[C:37]2[NH:36][C:35](=[O:39])[C:34]([CH3:41])([CH3:40])[N:33]=[C:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[F:48])[C:31]=2[CH:30]=[C:29]([N+:49]([O-:51])=[O:50])[CH:28]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O

Procedure:
From 120 g (0.33 mol) of 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in paragraph (c) of Example 1, 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 146°-147° (isopropanol/methylene chloride).