Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH:21]([C:23]([O:25]CC)=[O:24])[CH3:22])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:29])=[O:28])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH:21]([C:23]([OH:25])=[O:24])[CH3:22])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:28])=[O:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O)C(=O)O
Yield: 64.1 %

Procedure:
To a suspension of 2-(4-chlorophenyl)-6-[1-(ethoxycarbonyl)ethoxyl]-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (400 mg) in a mixture of ethanol (5 ml) and water (5 ml) was added aqueous 1N-sodium hydroxide solution (1.1) ml in one portion. The mixture was refluxed for half hour and concentrated in vacuo. The residue was dissolved in water and washed with ethyl ether. The aqueous layer was acidified with hydrochlonic acid. The separated oil was extracted with ethyl acetate. The organic layer was washed with brine, dried, and evaporated to dryness. The residue was crystallized from a mixture of n-hexane and ethyl acetate to yield 2-(4-chlorophenyl)-6-(1-carboxyethoxy)-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (240 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:18]=O)[CH3:13].Cl>CO>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:13]
Reactant: CCOc1cc(C=O)ccc1OCc1ccccc1
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: CCOc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-ethoxy-4-benzyloxybenzaldehyde 1.80 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.33 g.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[N:4][CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:32]1[N:33]([C:37]2[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=2[C:39](O)=[O:40])[N:34]=[CH:35][CH:36]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([C:39]([C:38]4[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=4[N:33]4[N:34]=[CH:35][CH:36]=[N:32]4)=[O:40])[CH2:14]3)[CH2:9]2)[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Cc1cncc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cncc(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(6-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 30) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H21N7O, 375.44; m/z found 376.1 [M+H]+. 1H NMR (CD3OD): 8.08-7.75 (m, 3H), 7.68-7.37 (m, 4H), 7.33-6.82 (m, 1H), 4.70-3.78 (m, 5H), 3.64-2.97 (m, 3H), 2.43-2.01 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]1=[O:25].[CH2:27](Br)[CH:28]=[CH2:29].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:29]([N:4]1[C:5]2[CH:6]=[C:7]3[N:22]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[NH:11][C:8]3=[CH:9][C:10]=2[C:2]([CH3:26])([CH3:1])[C:3]1=[O:25])[CH:28]=[CH2:27]
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4ccc(OC)cc4)nc3cc21
Temperature: 150 °C

Procedure:
A solution of N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)4-methoxy-benzamide (200 mg), allyl bromide (78 mg; 0.65 mmol) and K2CO3 (233 mg; 1.69 mmol) in acetone (3.2 ml) and N,N-dimethylformamide (1.6 ml) is stirred at 50° C. for 48 h. The mixture is filtered and concentrated in vacuo. The residue is suspended in acetic acid (3 ml), iron (150 mg; powder) is added and the resulting mixture is heated in a microwave apparatus at 150° C. for 900 s. After re-cooling the mixture is filtered and concentrated in vacuo. The desired compound is obtained by preparative RP-HPLC.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)C(C)C)(C)C.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1)=[O:24]>CN(C)C=O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1)=[O:24]
Reactant: CNCCO
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(methylamino)ethanol (10.7 g, 11.5 ml, 144 mmol, 1.5 equivalents, commercially available e.g. from Aldrich) in dry N,N-dimethylformamide (300 ml) was added N,N-diisopropylethylamine (25 ml, 18.5 g, 144 mmol, 1.5 equivalents). To this mixture was added 1,1-dimethylethyl 4-[(8-bromooctanoyl)amino]benzoate (38.1 g, 96 mmol, 1 equivalent) in dry N,N-dimethylformamide (250 ml) over 12 minutes. The mixture was then heated to and at about 60° C. for 4.25 hours. The mixture was then cooled and the solvent was removed by evaporation using high vacuum to give a golden oil. An attempt to partition this oil between water and ethyl acetate gave a cloudy organic phase and phase separation was poor; an oil separated out as a third layer, some of which was collected and evaporated to give crude product (16.69 g). The remaining emulsion was allowed to stand overnight, giving a clear organic layer which was decanted off, dried (MgSO4) and evaporated to give further crude product as a golden oil (28.11 g). Attempts to further extract the aqueous phase with ethyl acetate or dichloromethane gave an emulsion again, from which further crude product (about 10 g) was finally isolated. The combined crude product was purified by chromatography on silica gel (about 1400 ml of 7734 silica), eluting with 5% methanol in dichloromethane, then 8% methanol in dichloromethane, then 10% methanol in dichloromethane, and finally 20% and 30% methanol in dichloromethane, to afford the title compound as a white foam (28.4 g). LCMS showed MH+=393; TRET=2.52 min.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[CH2:2][C@@H:3]([CH2:5][CH2:6][CH:7]=C(C)C)[CH3:4].[BH4-].[Na+].C[OH:17]>>[OH:17][CH2:7][CH2:6][CH2:5][C@@H:3]([CH3:4])[CH2:2][C:1]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C[C@H](C)CCC=C(C)C
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)C[C@H](C)CCCO
Reaction time: 2 h

Procedure:
9.42 g (51 mmol) of methyl (R)-(+)-citronellate (9) are dissolved in 26 ml of methanol and saturated with 2.45 g (51 mmol) of 03 for 1 h at -30° C. Then 3.12 g (82 mmol) of NaBH4 (sic) are added in small portions with stirring. During the highly exothermic reaction, which lasts for 2 h, the temperature is kept between -20° C. and +10° C. Then cooling is discontinued and the mixture is brought to room temperature. A high proportion of the methanol is distilled off and to the residue are added 80 ml of CHCl3. This mixture is added at 0° C. to a vigorously stirred solution of 50 ml of conc. HCl in 100 g of ice. The chloroform phase is washed once with Na2CO3 solution and three times with H2O and is then dried over MgSO4 and concentrated. The crude product is distilled through a bulb tube.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH2:12].[CH3:14][C:15]1[CH:19]=[C:18]([CH2:20][C:21](O)=[O:22])[O:17][N:16]=1.CCOC(C)=O>O=P(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH:12][C:21](=[O:22])[CH2:20][C:18]1[O:17][N:16]=[C:15]([CH3:14])[CH:19]=1
Reactant: COC(=O)c1cc(C#N)ccc1N
Reactant: Cc1cc(CC(=O)O)on1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(C#N)ccc1NC(=O)Cc1cc(C)no1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 2-amino-5-cyano-benzoic acid methyl ester (1.50 g, 8.51 mmol) and (3-methyl-isoxazol-5-yl)-acetic acid (1.32 g, 9.36 mmol) in 40 ml of POCl3 was heated at 80° C. for 2 hr and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×40 ml), sat. NaHCO3 (40 ml), brine (40 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure gave 2.31 g (91%) of product as a light yellow solid: 1H-NMR (CDCl3; 400 MHz) δ 11.49 (s, 1H), 8.85 (d, 1H, J=8.8 Hz), 8.35 (d, 1H, J=2.0 Hz), 7.79 (dd, 1H, J=8.8, 2.0 Hz), 6.20 (s, 1H), 3.97 (s, 3H), 3.95 (s, 2H), 2.33 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C15H13N3O4, 300.1 (M+H), found 299.9.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[N:54][C:53]([Br:56])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:56][C:53]1[N:54]=[CH:55][C:50]([NH:49][C:40](=[O:42])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[N:51][CH:52]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1cnc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
A stirred solution of triphenylphosphine (8.57 g, 32.6 mmol) in anhydrous methylene chloride (110 mL) under nitrogen at 0° C. was treated with N-bromosuccinimide (5.80 g, 32.6 mmol). After 15 min, 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 9.00 g, 27.2 mmol) was added to the reaction. The mixture was allowed to warm to 25° C. After stirring at 25° C. for 10 min, the reaction was treated with 2-amino-5-bromopyrazine (7.92 g, 45.6 mmol) followed by pyridine (8.79 mL, 108.8 mmol). The mixture was allowed to stir at 25° C. for 1.5 h. At this time, the reaction was diluted with methylene chloride and then was washed with a 1N aqueous hydrochloric acid solution (200 mL) followed by a 10% aqueous potassium carbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 3/7 ethyl acetate/hexanes) afforded N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (10.02 g, 76%) as a white foam: mp 77–82° C. (foam to gel); (ES)+-HRMS m/e calcd for C19H21BrClN3O3S (M+H)+ 486.0249, found 486.0255.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Product: C#CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To but-3-yn-1-ol (40.0 g, 570.0 mmol) and 3,4-dihydro-2H-pyran (48.0 g, 570.0 mmol) in anhydrous dichloromethane (350 mL) was added pyridium p-toluenesulfonate (0.45 g, 1.80 mmol). The mixture was stirred at room temperature for 16 hours. Solvent was evaporated, and the residue was purified by vacuum distillation to give 2-but-3-ynyloxy-tetrahydro-pyran as a light yellow liquid. Yield: 60.0 g (68%).
Reaction SMILES: N[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.N([O-])=O.[Na+].OC1C(OC2C=CC=CC=2)=NC=C(OC)N=1.P(Cl)(Cl)([Cl:39])=O>>[Cl:39][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:5]=[C:4]([O:15][CH3:16])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc(Oc2ccccc2)c(N)n1
Agent: COc1cnc(Oc2ccccc2)c(O)n1
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cnc(Oc2ccccc2)c(Cl)n1

Procedure:
The 2-amino substituent of Step A product when treated with sodium nitrite as described in Step E of Preparation 81 is converted to the 2-hydroxy group. Treatment of the 2-hydroxy-3-phenoxy-6-methoxypyrazine with phosphorus oxychloride by the method of Preparation 13, Step B, gives 2-chloro-3-phenoxy-6-methoxypyrazine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[N:19]([CH3:20])[C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=1[C:24]([N:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[C:21]([C:18]1[N:19]([CH3:20])[C:15]([NH:14][C:8]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:7]=2[F:6])=[C:16]([C:24]([N:26]2[CH2:29][CH:28]([O:30][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27]2)=[O:25])[CH:17]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(C(=O)N2CC(O)C2)c(Nc2ccc(I)cc2F)n1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(C(=O)N2CC(OS(C)(=O)=O)C2)c(Nc2ccc(I)cc2F)n1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
Methane sulfonyl chloride (0.026 ml, 0.33 mmol) was added dropwise at 0° C. to a stirred solution of Example 27 (102 mg, 0.22 mmol) and triethyl amine (0.047 ml, 0.33 mmol) in CH2Cl2 (1.2 mL). After stirring for 10 min at 0° C., the reaction mixture was allowed to warm up at room temperature. After stirring for 2 hours, the reaction mixture was washed with a saturated solution of NaHCO3, extracted with CH2Cl2. The organics were washed with and brine, dried (MgSO4), and concentrated. Purification by silica gel chromatography gave 100 mg (84%) of the title compound as beige solid. MS (ES) [m+H] calc'd for C18H19FIN3O5S, 536; found 536.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:15][C@@H:14]3[C@@H:11]([CH2:12][N:13]3C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[N:6][C:7]=1[Cl:8].[C:23]1([S:29]([OH:32])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)CC>[C:23]1([S:29]([OH:32])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:15][C@@H:14]3[C@@H:11]([CH2:12][NH:13]3)[CH2:10]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(c3cnc(Cl)c(Cl)c3)C[C@H]21
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCCO
Product: Clc1cc(N2C[C@@H]3CN[C@@H]3C2)cnc1Cl
Temperature: 75 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
Tert-butyl (1R,5S)-3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (642 mg) in 1-propanol (8 mL) was treated with benzenesulfonic acid (516 mg) and heated at 75° C. with stirring for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the wetcake was dried in a vacuum oven at 50° C. to provide 292 mg of the title compound. 1H NMR (DMSO, 400 MHZ) δ 2.99 (dd, J=10, 6 Hz, 1H), 3.09 (dd, J=12, 5 Hz, 1H), 3.39 (m, 1H), 3.56 (m, 1H), 3.89 (d, J=11 Hz, 1H), 4.05–4.11 (m, 1H), 4.94 (m, 1H), 7.29 (m, 3H), 7.55 (d, J=3 Hz, 1H), 7.58 (m, 2H), 7.97 (d, J=3 Hz, 1H), 8.80 (br, 1H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C@H:14]([CH2:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].C(N(CC)CC)C.O([Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])S(C(F)(F)F)(=O)=O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C@H:14]([CH2:15][CH:16]([O:23][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(O[Si](C)(C)C(C)(C)C)CC[C@@H]4[C@H]3CC[C@]12C
Reaction time: 0.42 h
Yield: 87.4 %

Procedure:
To a solution of 17β-acetyloxy-5α-estran-3-one (1.595 g, 5 mmol) in dry dichloromethane (30 mL) was added with stirring at ice-water bath temperature, triethyl amine (2 mL) followed by t-butyldimethylsilyl triflate (2.64 g, 10 mmol). The solution was stirred for 25 min, then diluted with dichloromethane (20 mL) and washed with satd.aq. NaHCO3 (30 mL), brine (30 mL) and dried over Na2SO4. The solvent was removed to yield a solid, which was purified by chromatography (silica gel, dichloromethane, pretreated with 1% triethyl amine in hexanes) to get 1.9 g (87%) of pure product as colorless crystals, m.p. 89°-90° C.
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]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=O)[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:31]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:41]2)=CC=1>C1(C)C=CC=CC=1>[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]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[S:41])[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:31]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Solvent: Cc1ccccc1
Product: S=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
Dissolve 0.50 g (0.12 m mole) of 8-chloro-11-[1-(1-(3-pyridyl)methylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine (Example 2 of Table 2) and 0.5 g (0.12 m mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) in 15 mL of toluene and stirr for 18 hours at room temperature and 18 hours at 80° C., under nitrogen. Filter the reaction mixture and concentrate under vacuo. Disolve the residue in 50 mL of 1N HCl and extract with 200 mL of CH2Cl2. The water layer was neutralized with Na2CO3 and extracted with CH2 Cl2. The organic layer was dried over MgSO4 and concentrated under vacuo giving the product as a white solid, mp=92°-93° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][NH2:20]>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][NH:20][C:2]1[C:11]2[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: CSc1cccc2c(Cl)cc(C)nc12
Product: CSc1cccc2c(NCc3ccc(F)c(F)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methylsulfanylquinoline and 3,4-difluorobenzylamine.
Reaction SMILES: [OH:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@H:2]([OH:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)CO1
Reactant: COCCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Product: COCCOc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](O)CO3)ccc2F)c(F)c1
Yield: 71 %

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-hydroxy-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 94), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 191 as a white solid (73 mg, 71%). 1H NMR (400 MHz, d6-DMSO) δ 10.22 (s, 1H), 8.25 (dd, J=8.6, 4.0 Hz, 1H), 8.12 (t, J=8.9 Hz, 1H), 7.82 (s, 1H), 6.97 (d, J=10.2 Hz, 2H), 4.79 (dd, J=10.8, 3.4 Hz, 2H), 4.26-4.20 (m, 2H), 3.90-3.67 (m, 4H), 3.73-3.67 (m, 2H), 3.63 (dd, J=12.8, 5.8 Hz, 1H), 3.62-3.02 (m, 3H), 2.73-2.64 (m, 1H), 2.00-1.92 (m, 1H), 1.92-1.79 (m, 1H), 1.79-1.72 (m, 1H), 1.55-1.42 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 536 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]([CH3:12])[CH3:11].C(O)(C)C.C(=O)=O.C([Li])CCC.[B:25](OC)([O:28][CH3:29])[O:26][CH3:27]>O1CCCC1>[CH3:11][N:10]([CH3:12])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:25]([O:28][CH3:29])[O:26][CH3:27]
Reactant: CN(C)CCc1ccccc1Br
Reactant: COB(OC)OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COB(OC)c1ccccc1CCN(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
19.0 g (83.2 mmol) of the [2-(2-bromophenyl)ethyl]dimethylamine prepared according to example 10 (2nd stage) were dissolved in 300 ml tetrahydrofuran and the solution was cooled to −70° C. in a cooling bath (isopropanol/dry ice). 60 ml (95.7 mmol) butyllithium solution (1.6 M in hexane) were added dropwise under nitrogen such that the temperature did not rise above −60° C. After the mixture had been stirred at −70° C. for two hours, 28 ml (250 mmol) trimethyl borate were also added dropwise such that the temperature did not rise above −60° C. The mixture was warmed to 25° C. in the course of 15 hours and the solution was concentrated on a rotary evaporator (500-10 mbar) without heat being supplied. The residue was taken up in 200 ml n-hexane, the mixture was stirred for one hour and filtered over an inert gas frit under nitrogen and the filtrated was concentrated on a rotary evaporator (500-10 mbar) without heat being supplied. 14.1 g dimethyl 2-(2-dimethylaminoethyl)benzeneboronate (76.5% of theory) were obtained in this manner.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[C:13]3[CH2:19][NH:18][C:17]([CH3:21])([CH3:20])[C:14]=3[NH:15][N:16]=2)[N:6]=1)[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:31][C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[C:13]3[CH2:19][N:18]([C:32]([Cl:31])=[O:34])[C:17]([CH3:20])([CH3:21])[C:14]=3[NH:15][N:16]=2)[N:6]=1)[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOc1ccnc(Nc2n[nH]c3c2CNC3(C)C)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccnc(Nc2n[nH]c3c2CN(C(=O)Cl)C3(C)C)n1
Temperature: 22 °C

Procedure:
To a −78° C. solution of N-(4-ethoxypyrimidin-2-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine hydrochloride (0.300 g, 1.09 mmol) in CH2Cl2 (15 mL) and diisopropylethylamine (0.952 mL, 5.47 mmol) was added triphosgene (0.227 g, 0.766 mmol) in CH2Cl2 (5 mL) dropwise over 10 min. The reaction was quenched with H2O (10 mL), warmed to 22° C., and made pH 8-9 with NaHCO3. The aqueous layer was extracted with CH2Cl2 (2×30 mL) and the combined organic layers washed with brine (1×30 mL), dried over MgSO4, and concentrated to give the desired product M1(i) as a brown solid (0.35 g, 95%). Mass Spectrum: Calcd for C14H18ClN6O2 (M+H): 337. Found: 337.