Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:10][CH2:9][C@@H:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[OH:11])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1ccc([C@@H](O)CO)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1ccc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of (R)-1-(6-methylpyridin-3-yl)ethane-1,2-diol (13.72 g, 0.085 mol), 1H-imidazole (13.55 g, 0.197 mol), and CH2Cl2 (180 mL) at 0° C. was added tert-butyldimethylsilyl chloride (15.31 g, 0.098 mol). The reaction mixture was stirred at 0° C. for 30 minutes, then warmed to room temperature and stirred overnight. The mixture was washed with water (300 mL) and extracted with CH2Cl2. The combined organic layers were dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (0-50% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6](=[O:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CCO.O>[C:1]([O:4][CH2:5][CH:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)OCC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added the crude 3a in EtOH solution (about 153 mL) reserved from the previous step at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (2.35 g) in water (60 mL) was added at below −8° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed completed as determined by TLC. 1N HCl aqueous solution (60 mL) was added at below 10° C. The mixture was warmed to 20-30° C., and H2O (183 mL) was added at this temperature. After being stirred at 20-30° C. for 1 hr, the mixture was further cooled to 0-5° C. and stirred for 1 hr. The mixture was filtered, and the filtered cake was washed with cold 50% EtOH aqueous solution (30 mL). The combined filtrate and washing was concentrated at 40-50° C. under reduced pressure to afford crude 4a as a white powder (18.7 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH2:22]([N:24]1[CH2:29][CH2:28][P:27]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[C:33]([O:38][CH3:39])[CH:32]=2)(=[O:30])[CH2:26][CH2:25]1)[CH3:23].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([P:27]3(=[O:30])[CH2:28][CH2:29][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26]3)=[CH:32][C:33]=2[O:38][CH3:39])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CCN1CCP(=O)(c2ccc(N)c(OC)c2)CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: CCN1CCP(=O)(c2ccc(Nc3nnc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)c(OC)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[N:11][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][S:2]([CH3:1])(=[O:4])=[O:3])=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(F)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(F)cn1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Add methanesulfonyl chloride (1.8 mL, 23.5 mmol) to a solution of (5-fluoro-pyridin-2-yl)-methanol (2.5 g, 19.7 mmol) and triethylamine (8.2 mL, 59.0 mmol) in DCM (150 mL) at 0° C. under nitrogen. Stir the mixture for 30 min and concentrate in vacuo. Dilute with water (20 mL) and extract the mixture with EtOAc (3×50 mL). Combine the organic extracts and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc to obtain the desired intermediate (2.2 g, 54%).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([S:24][CH:25]([C:29](O)=[O:30])[C:26](O)=[O:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[OH:30][C:29]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:26](=[O:27])[C:25]=1[S:24][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: O=C(O)C(Sc1cccc2ccccc12)C(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1Sc1cccc2ccccc12

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(1-naphthyl)thio]propanedioic acid (1.61 g, 5.07 mmol). m.p. 242-243° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.83 (s, 1H), 7.19 (d, 1H), 7.39 (t, 1H), 7.64-7.42 (m, 5H), 7.69 (d, 1H), 7.83 (m, 2H), 7.94 (d, 1H), 8.28 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1>CO.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)c1
Agent: [Pd]
Solvent: CO
Product: Cn1cnc(-c2cc(Oc3ccc(N)nc3)ccn2)c1
Yield: 90.5 %

Procedure:
A solution of 2-(1-methyl-1H-imidazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.61 g, 5.42 mmol) in MeOH (30 mL) was treated with 10% Pd/C (50% w/w water, 0.576 g, 0.542 mmol) and hydrogenated (50 psi) overnight. The solids were removed via filtration through diatomaceous earth, washed with warm MeOH and the filtrate was concentrated to dryness to afford 5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (1.311 g, 91%). 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, J=5.7 Hz, 1H), 7.81 (d, J=2.9 Hz, 1H), 7.65 (d, J=1.3 Hz, 1H), 7.58 (s, 1H), 7.29 (dd, J=8.9, 3.0 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H), 6.73 (dd, J=5.7, 2.6 Hz, 1H), 6.52 (d, J=8.9 Hz. 1H), 6.03 (s, 2H), 3.67 (s, 3H); MS (ESI) m/z: 268.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: CCS(=O)(=O)Cl
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: CCS(=O)(=O)NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in example 1 but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and ethanesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)([OH:3])=O.[CH3:48][N:49](C)[C:50](=O)C=C>>[CH3:48][N:49]([CH3:50])[C:1](=[O:3])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNCCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=CC(=O)N(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCNCCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-carboxyethylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using N,N-dimethylacrylamide as the Michael aceptor reagent in the first step. The product was isolated as a white solid (9 mg, 50%). LCMS: m/e 672.47 (M+H)+, 2.33 min (method 2). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.88 (s, 1H), 4.76 (s, 1H), 3.86-3.59 (m, 4H), 3.51-3.37 (m, 2H), 3.07 (s, 3H), 2.99 (s, 3H), 2.95 (t, J=5.6 Hz, 2H), 2.90-2.76 (m, 1H), 2.37-1.22 (m, 22H), 1.78 (s, 3H), 1.20 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][CH2:15][OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][CH:15]=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)C(CCO)CC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)C(CC=O)CC2
Yield: 98 %

Procedure:
Prepared in an analogous manner to that described in Example 4, by oxidizing 2-(6-tert-butyl-1-indanyl)-1-ethanol (8.53 g, 32.1 mmole, 82.3% pure) in dichloromethane (50 ml), by means of PCC (Fluka, 15.0 g, 68 mmole) in dichloromethane (100 ml). After the treatment described and bulb-to-bulb distillation (120°/15 Pa), there was obtained the above-mentioned compound with a purity of 84% (6.01 g, yield 72.7%). Further purification by chromatography provided the desired compound 98% pure, presenting the following analytical characters:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1.ClC1C=C(C=CC=1)C(O)=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]3)[C:10]3=[N+:11]([O-:33])[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc[n+]([O-])c32)CC1
Reaction time: 1.58 h
Yield: 51.8 %

Procedure:
8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (5 g, 13.06 mmol) was dissolved in CH2Cl2 at −10C. 3-Chlorobenzoic acid (4.9 g, 15.67 mmmol) was then added and the reaction mixture stirred for 95 minutes. The reaction mixture was taken up in CH2Cl2 and extracted with sodium bisulfite, 10% NaOH. The crude reaction product was purified on silica gel eluting first with 1% and then with 2% MeOH in CH2Cl2 to give the title compound (2.7 g, MH+ 399).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]1[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]1[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=1)=[O:19]
Reactant: Cn1cncc1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cn1cncc1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 79 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N-[(1-methyl-1H-imidazol-5-yl)methoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 101 (0.40 g, 0.90 mmol) and Pd/C (0.13 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give a residue which was subjected to chromatography to give 102 (0.21 g, 75%) as a white foam.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.CO.[C:12](=O)(O)[O-:13].[Na+].C(=O)=O>O>[CH3:12][O:13][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([Cl:9])[N:1]=1
Reactant: O=C([O-])O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(Cl)nc(Cl)n1
Temperature: 3 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
36.8 g (0.2 mol) of cyanuric chloride are added in the course of 2 hours, at 0°-5° C., to a mixture of 200 ml of methanol, 25 ml of water and 33.6 g (0.4 mol) of sodium bicarbonate. The reaction mixture is stirred, first for one hour at about 3° C. and then for about 30 minutes at 30° C., until the evolution of CO2 has ceased. The white suspension is washed with 100 ml of water and the product is filtered off and dried at 60° C. in a drying cabinet. Recrystallisation from hexane yields 19.6 g of 2-methoxy-4,6-dichloro-1,3,5-triazine with a melting point at about 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C=NC(=O)c1c(Cl)cccc1Cl
Yield: 88 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2,6-dichlorobenzamide (1.00 g, 5.26 mmol), oxalyl chloride (0.795 g, 6.31 mmol) and toluene (10 mL) to afford 1.00 g of desired product.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([CH:35]1[CH2:37][CH2:36]1)[NH2:34]>>[CH:35]1([C:33]2[N:34]=[C:28]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:12]3)[O:30][N:32]=2)[CH2:37][CH2:36]1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)C1CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)CC1

Procedure:
100 mg (about 0.153 mmol) of the compound from Example 108A and 30 mg (0.306 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 312 mg (41% of theory)
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22]#[N:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2].C(N(CC)CC)C.[SH2:31]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[S:31])[NH2:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2]
Reactant: S
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reaction time: 16 h

Procedure:
A solution of 10-[(2RS)-1-(N-ethyl-N-methyl-amino)-2-propyl]-2-phenothiazinecarbonitrile (3 g) and triethylamine (1.3 cc) in anhydrous pyridine (60 cc) is treated with excess hydrogen sulphide, and stirring is then continued for 16 hours at a temperature in the region of 20° C. The solution obtained is purged with a stream of nitrogen for 1 hour, poured into ethyl acetate (100 cc), washed with distilled water (3×200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at.40° C. The residual brown oil is purified by chromatography on a column (height: 40 cm; diameter: 3 cm) of silica gel (0.2-0.06 mm), eluting successively with methylene chloride (1 liter), a mixture (95:5 by volume) (1 liter) of methylene chloride and methanol and a mixture (80:20 by volume) (3 liters) of methylene chloride and methanol, and collecting 150-cc fractions. Fractions 26 to 30 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-1-(N-Ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (2.15 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7]3([CH2:35][O:34][C:26]4[CH:27]=[C:28]5[C:29](=[CH:33][C:25]3=4)[CH2:30][CH2:31][O:32]5)[C:8]2=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(F)c2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(F)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 7-fluoro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (70%) as a colorless solid: mp 183-184° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ7.45-7.22 (m, 10H), 7.13-7.05 (m, 3H), 6.98 (s, 1H), 6.44-6.43 (m, 2H), 4.91 (d, J=9.5 Hz, 1H), 4.80 (d, J=9.5 Hz, 1H), 4.51 (t, J=8.9 Hz, 2H), 2.97 (t, J=8.6 Hz, 2H); MS (ES+) m/z 463.9 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)[N:16]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([NH:23][C:24]([NH:12][S:9]([C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3][O:2][CH3:1])(=[O:11])=[O:10])=[O:25])[N:18]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COCc1ccsc1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COCc1ccsc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.41 g of 3-(methoxymethyl)thiophene-2-sulfonamide and 0.55 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate in 20 mL of acetonitrile is added 0.3 mL of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). After being stirred for 2 hours at ambient temperature and pressure, the reaction mass is poured onto 25-50 g of ice and the resultant mixture acidified to pH 3 by the addition of hydrochloric acid. The desired solid product can be isolated by filtration. Alternatively, it can be extracted into methylene chloride which is then dried over magnesium sulfate, filtered and evaporated to dryness to yield the desired product is sufficiently pure form for the purposes of this invention.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][C:24]=2[Cl:26])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1OCc1ccccc1
Yield: 51 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454, which is incorporated herein by reference in its entirety) (11 g, 41.6 mmol) and 2,4-dichlorophenylboronic acid (11.9 g, 62.3 mmol) were treated substantially as described in Part A of Example 19a to give 8.0 g (51%) of 2-benzyloxy-4-(2,4-dichloro-phenyl)-3-nitro-pyridine: MS (AP) m/z 375.2 [(M+H)+, 100].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[O:19]>C(OCC)(=O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: Cc1cccc(C(=O)CBr)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-methylacetophenone (R. Yveline, G. Gerard, and M. Geroges, Chem.Pharm.Bull., 1992, 40, 1170.). tlc: Rf=0.5 (25% ethyl acetate in hexanes)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=2)[CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=3)[CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: CCOc1ccc(N(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9](=[O:24])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=2[F:23])[O:11][CH2:12][CH3:13])=[C:5]([OH:27])[CH:4]=1)#[N:2].I[CH2:29][C:30]([NH2:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:30]([CH2:29][O:27][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:26]=[CH:25][C:6]=1[CH2:7][NH:8][C:9](=[O:24])[CH:10]([C:14]1[C:15]([F:23])=[CH:16][C:17]([O:21][CH3:22])=[CH:18][C:19]=1[F:20])[O:11][CH2:12][CH3:13])(=[O:31])[NH2:32]
Reactant: NC(=O)CI
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1O)c1c(F)cc(OC)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1OCC(N)=O)c1c(F)cc(OC)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide was alkylated with iodoacetamide/cesium carbonate in DMF to give (RS)-N-(2-carbamoylmethoxy-4-cyano-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide as a colorless solid. MS 434.3 ([M+H]+)