Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:16](Br)[CH:17]=[CH2:18].C(Cl)(Cl)Cl>CS(C)=O>[CH2:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: C=CCn1c2ccccc2c2ccccc21
Yield: 100 %

Procedure:
Carbazole (10.1 g, 0.057 mol) and potassium hydroxide (88% wt pellets, crushed, 7.1 g, 0.11 mol) were stirred in 100 mL DMSO at 50° C. for 30 min before dropwise addition of allyl bromide (14.7 g, 0.118 mol). After 15 min the reaction mixture was poured into a 500 mL separatory funnel containing 100 mL chloroform and washed 5 times with 200 mL water to give, after solvent evaporation at 60° C. under reduced pressure, compound 15 in >99% purity as a dark brown, viscous syrup which solidified upon cooling (11.9 g, 0.057 mol, 100% yield). 1H NMR (300 MHz, CDCl3): δ=8.14-8.06 (m, 2 carbazole H), 7.49-7.32 (m, 4 carbazole H), 7.28-7.19 (m, 2 carbazole H), 6.04-5.90 (m, CH═CH2), 5.19-5.10 (m, Z-HCH═CH), 5.07-4.97 (m, E-HCH═CH), 4.92-4.85 (m, NCH2). 13C NMR (300 MHz, CDCl3): δ=140.34, 132.27, 125.67, 122.90, 120.33, 119.00, 116.74, 108.74, 45.21.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N3CCN(C)CC3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(4-methyl-piperazin-1-yl)-aniline
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([O-:26])=[O:25]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:36]2[CH2:37][CH2:38][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N+:24]([O-:26])=[O:25])[CH2:34][CH2:35]2)=[O:11])[N:3]=1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: Cc1cc(C)n(CC(=O)O)n1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3[N+](=O)[O-])CC2)n1
Reaction time: 1 h
Yield: 64 %

Procedure:
To (3,5-dimethyl-pyrazol-1-yl)-acetic acid (0.140 g, 0.908 mmol) in DMF is added carbonyl diimidazole (0.140 g, 0.863 mmol) in one portion. The mixture is stirred for 1 h. To this is added 1-(2-nitro-phenyl)-piperazine (0.197 g, 0.950 mmol). The mixture is stirred for 14 h and then diluted with 100 mL EtOAc. The reaction is quenched with 20 mL of saturated NH4Cl, washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried (MgSO4), filtered and concentrated to give 2-(3,5-dimethyl-pyrazol-1-yl)-1-[4-(2-nitro-phenyl)-piperazin-1-yl]-ethanone in 64% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH2:26])=[CH:21][CH:20]=[CH:19]2.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH:26][S:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:35])=[O:34])=[CH:21][CH:20]=[CH:19]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Solvent: c1ccncc1
Product: COc1cc2nccc(Oc3ccc4c(NS(=O)(=O)c5ccccc5)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)naphthalen-1-amine (50 mg, 0.144 mmol) and benzenesulfonylchloride (25 mg, 0.144 mmol) were dissolved in pyridine (0.6 mL) then stirred at RT for 3 days. The reaction mixture was concentrated under vacuum. The crude material was purified by silica gel chromatography (2% to 4% MeOH in DCM) to give N-(6-((6,7-bis(methyloxy)-4-quinolinyl)oxy)-1-naphthalenyl)benzenesulfonamide as a tan solid. MS (ESI pos. ion) m/z: 487.1 (+H). Calc'd for C27H22N2O5S−486.55.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[CH:11]=2)[N:3]=1.[CH:18]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+].O>CC(C)=O>[Cl:8][C:6]1[N:7]=[C:2]([NH:25][CH:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[CH:11]=2)[N:5]=1
Reactant: NC1CCCCCC1
Reactant: Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1F

Procedure:
To 156a (1.0010 g, 3.7 mmol) dissolved in acetone (20 mL) was added a solution of N-cycloheptylamine (0.5 mL, 3.7 mmol) in acetone (5 mL) followed by addition of 2.5 N NaOH (1.5 mL, 3.7 mmol) and water (4 mL). The reaction mixture was allowed to stir at reflux for 3 hours under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine, and dried over potassium carbonate. After filtering, the sample was concentrated, and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded a white solid (156b, 1.144 g, 88%), mp 149° C.; HPLC: Inertsil ODS-3V C18, 30:70 [KH2PO4 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 28.9 min, 90.4% purity; MS (TOF MS ES+): m/z 427 (40.2), 351 (32.2), 350 (M+H, 100).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][NH2:16].C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][NH:16][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)c(F)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@@H]1C[C@H]1c1c(F)ccc2nn(C)cc12
Yield: 85.7 %

Procedure:
To a solution of trans-1-[2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine (95.0 mg, 0.433 mmol) and triethylamine (72.4 μL, 0.520 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (45.1 μL, 0.477 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (97 mg, yield 86%).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:29]([O:31][C:32]1C=CC([N+]([O-])=O)=CC=1)=[O:30]>ClCCl>[CH3:32][O:31][C:29](=[O:30])[NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
To a solution of (R)—N2-indan-1-yl-quinoline-2,6-diamine (1.2 g, 4.36 mmol) and pyridine (0.35 mL, 4.36 mmol) in dichloromethane (25 mL) at 0° C. was added 4-nitrophenyl chloroformate (878 mg, 4.6 mmol) and the mixture was stirred at 23° C. for 2 h resulting in a yellow suspension. Added tetrahydrofuran, filtered the solid off, dissolved in dichloromethane and methanol, coated on silica gel. Removal of the solvent in vacuum left a brown foam, which after silica gel column chromatography was crystallized from dichloromethane/diethyl ether to give the title compound as a yellow foam (500 mg, 34%); MS: m/e=334.2 (M+H+).
Reaction SMILES: [OH-:1].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1>CS(C)=O.O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([OH:1])=[CH:5][C:6]=1[O:13][CH3:14])([O-:12])=[O:11]
Reactant: [OH-]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(O)ccc1[N+](=O)[O-]
Reaction time: 2.5 h

Procedure:
A solution of sodium hydroxide was added to a stirred solution of 4-fluoro-2-methoxynitrobenzene (11.1 g.) in DMSO (60 ml.) at ambient temperature and the mixture was heated at 85 degC. for 2.5 hr. The cooled solution was diluted with water (100 ml.) and extracted with ether (3×100 ml.) The combined ethereal solution was extracted with 2n NaOH (3×75 ml.) and the combined aqueous phase brought to pH 2 by the addition of 2N HCl. The precipitated product was collected and washed with water. The product was dried over phosphorous pentoxide. Yield 7.4 g. m/Z 170.1(M+H). It was used without further purification in the next step (cf Example 1c).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C(N(CC)C(C)C)(C)C.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25]Br)([CH3:19])([CH3:18])[CH3:17].[C:28]([C:30]1[CH:60]=[CH:59][C:33]([O:34][C:35]2[N:49]=[C:48]([O:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)[CH:47]=[CH:46][C:36]=2[C:37]([NH:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:38])=[CH:32][CH:31]=1)#[N:29]>CN(C=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25][N:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:37]([C:36]2[C:35]([O:34][C:33]3[CH:32]=[CH:31][C:30]([C:28]#[N:29])=[CH:60][CH:59]=3)=[N:49][C:48]([O:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[O:38])[CH2:41][CH2:42]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)NC3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Temperature: 45 °C
Yield: 88.7 %

Procedure:
0.117 g (0.85 mmol) of K2CO3 and N,N-diisopropylethylamine 0.072 g (0.56 mmol) followed by 0.201 g (0.85 mmol) of (3-bromo-propyl)-carbamic acid tert-butyl ester, dissolved in 5 ml of DMF, were added to a stirred solution of 0.373 g (0.85 mmol) of 2,6-bis-(4-cyano phenoxy)-N-piperidine-4-yl nicotinamide, dissolved in 5 ml of DMF over a period of 15 min at 20° C. Reaction mixture was allowed to attain RT and heated to 45° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was partitioned between water (150 ml) and ethyl acetate (150 ml). The organic phase was washed with 1 M Na2CO3 and saturated brine solution, and dried over sodium sulphate. The solution was concentrated and the oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.45 g of the required product. Percentage purity (LCMS): 72.5%, (M+1)=596.2+1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][P:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:14]=1)([CH3:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([P:10]([CH3:12])([CH3:9])=[O:11])=[CH:14][C:15]=2[S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:7]=1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1N
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1cc(Cl)ncn1

Procedure:
To a solution of 4,6-dichloropyrimidine (1.31 mmol) in 1 mL of DMF is added 4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline: (1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol). The mixture is heated at 110° C. until formation of the desired compound. The reaction mixture is basified with saturated sodium bicarbonate solution. The suspension is filtered and washed with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]([F:4])=[CH2:3].[N+](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>ClCCl>[Cl:1][C:2]1([F:4])[CH2:3][CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(F)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CC1(F)Cl
Yield: 91 %

Procedure:
16.9 mg of tetrakis(triphenylacetato) dirhodium was added to 10 ml of dichloromethane and dissolved therein. Then 370 mg of powdery Molecular Sieves 4A was added thereto. The reaction container was soaked in a dry ice/acetone bath and 1.0 g of 1-chloro-1-fluoroethylene was dissolved in the mixture. While maintaining the temperature of this solution at -35° C. to -40° C., 5.3 ml of a solution of 2.5 mmol of ethyl diazoacetate in dichloromethane was dropped thereinto under an argon gas atmosphere. The addition was made in such a manner that a half of the solution was dropped within 15 minutes and another half was dropped within 30 minutes. After the completion of the addition, the reaction mixture was slowly returned to room temperature. When analyzed by gas chromatography, it was found out that the reaction conversion ratio was 100%, the yield was 91% and the ratio of cis:trans was 1.59:1.0. The analytical data of the title product are as follows.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH3:8])[CH:4]=[N:3]1.[BrH:10].BrBr>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:10][CH2:8][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: Br
Reactant: CC(=O)c1cnn(C)c1
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cn1cc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1-methyl-1H-pyrazol-4-yl)ethanone (0.602 g, 4.85 mmol) in chloroform (20 mL) and of 33% HBr in acetic acid (3.92 mg, 0.05 mmol) was added dropwise a chloroform solution containing Br2 (0.262 mL, 5.09 mmol) via an addition funnel. The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The crude solid was triturated in ethyl acetate, filtered, washed and dried in vacuo. The free base was obtained by triturating the product in 5% NaHCO3 for 2 h. The solid that formed were collected by filtration, washed with water and isopropyl alcohol and then dried in vacuo. Isolation gave 874 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[F:12][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1c(F)ccc(F)c1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1c(F)c(F)cc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
2,3,6-Trifluorobenzoic acid (21.0 g) is added to conc. sulfuric acid (120 ml) under ice-cooling. To the mixture is added dropwise a solution of potassium nitrate (14.5 g) in conc sulfuric acid (30 ml) at below 20° C. After the addition, the mixture is stirred at room temperature for one hour. The reaction mixture is poured into ice water and extracted with diethyl ether. The extract is dried over magnesium sulfate, and then the solvent is distilled off. The residue is recrystallized from dichloromethane--n-hexane to give 2,5,6-trifluoro-3-nitrobenzoic acid (22 g), as colorless prisms, m.p. 98°-99° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@@H:6]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[O:7][C@H:8]2[CH2:14][NH:15][CH:16]=[O:17].[Cl:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([NH:31][CH:32]([CH3:36])[CH2:33][CH:34]=O)=[O:30])=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH:32]([CH3:36])[CH2:33][CH2:34][N:21]2[CH2:20][CH2:19][CH:18]([C@@H:6]3[CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:12]([CH3:13])[C:3]=4[O:2][CH3:1])[C@H:8]([CH2:14][NH:15][CH:16]=[O:17])[O:7]3)[CH2:23][CH2:22]2)=[O:30])=[CH:37][CH:38]=1
Reactant: CC(CC=O)NC(=O)c1ccc(Cl)cc1
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(CCC(C)NC(=O)c3ccc(Cl)cc3)CC1)O[C@H]2CNC=O

Procedure:
Stir a suspension of N-((1R,3S)-5-methoxy-6-methyl-3-(4-piperidinyl)-1-isochromanylmethyl)formamide (1.0 mmol) with 4-Chloro-N-(1-methyl-3-oxo-propyl)-benzamide (3.0 mmol) and sodium triacetoxyborohydride (3.0 mmol) in dichloromethane (5 mL) at room temperature overnight. Apply the reaction mixture directly to a 5 g SCX column and elute and concentrate the appropriate fractions to obtain the title compound. Use the compound directly for the next step.
Reaction SMILES: [N:1]12[CH2:8][CH:7]([NH:9][C:10]([C:12]3[C:17]4[N:18]=[C:19]([NH:21]C(=O)OC(C)(C)C)[O:20][C:16]=4[CH:15]=[CH:14][CH:13]=3)=[O:11])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]12[CH2:8][C@@H:7]([NH:9][C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[O:20][C:19]([NH2:21])=[N:18][C:17]=34)=[O:11])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: CC(C)(C)OC(=O)Nc1nc2c(C(=O)NC3CN4CCC3CC4)cccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 4-(quinuclidine-8-yl-carbamoyl)benzoxazole-2-yl-carbamate (0.210 g, 0.54 mmol), in CH2Cl2 (5 mL) was added TFA(2 mL) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated and the crude material was treated with aqueous NaHCO3 to adjust the pH to 7 and then extracted with CH2Cl2 (5×50 mL). The combined organic phase was concentrated and purified by preparative TLC (90:9:1 CH2Cl2/CH3OH/concentrated NH4OH) to afford (S)—N-(quinuclidine-8-yl)-2-aminobenzoxazole-4-carboxamide which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[C:5]2[CH3:12].C[Mg]Cl.CC([Li])CC.CN(C)[CH:23]=[O:24].Cl>C1COCC1>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH3:12])=[N:6][NH:7]2)=[CH:3][C:2]=1[CH:23]=[O:24]
Reactant: Cc1n[nH]c2cc(F)c(Br)cc12
Reactant: CN(C)C=O
Agent: C[Mg]Cl
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cc1n[nH]c2cc(F)c(C=O)cc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 30 g (131 mmol) 5-bromo-6-fluoro-3-methyl-1H-indazole [preparation described in WO 2005/085227-A1, Example 104c); also commercially available, CAS Reg.-No. 864773-66-0] in THF (525 ml) was cooled to −45° C. A solution of methylmagnesium chloride in THF (3 M; 50.2 ml, 151 mmol) was added dropwise at −45° C., and the resulting solution was stirred for 40 min at this temperature. Using a dosing pump, 253 ml (354 mmol) of 2-butyllithium solution (1.4 M in cyclohexane) were added so that the temperature did not exceed −40° C. The resulting mixture was stirred for 30 min at −40° C., and then 30.2 ml (393 mmol) N,N-dimethylformamide were added dropwise keeping the temperature at −40° C. The resulting mixture was stirred for 30 min at −40° C., then allowed to warm up to room temperature, and slowly poured into a volume of 2.8 L of 2 N hydrochloric acid cooled to 5° C. (ice-water bath). The mixture was extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane and purified by chromatography on silica gel (eluent: pentane/ethyl acetate 6:4 v/v) to afford 19.6 g (78% of th.) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH2:11][N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=2)=[O:19])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(CNc1ccccc1)Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: O=C(CN(C(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide (73 mg) in THF (3.1 mL) was added tiethylamine (52 μL) and 3-trifluoromethylbenzoyl chloride (62 mg) and the reaction mixture was stirred at room temperature for 30 minutes. To the mixture was then added water under precipitation occurred and the mixture was stirred for 5 minutes. Then the precipitate was isolated by filtration and washed with a mixture water-ethanol (1:1) to yield the title compound as a white solid (64 mg, mp=130-132° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.Cl[C:20]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: Nc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Temperature: 100 °C

Procedure:
To a resealable tube was added 4-aminophenol (1.3 g, 12 mmol), cesium carbonate (7.8 g, 24 mmol), and DMSO (16 ml, 0.75 M). The mixture was heated to 100° C. for 5 minutes, and then 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (2.5 g, 12 mmol) was added, and the reaction mixture was heated to 130° C. overnight. Upon completion, as judged by LCMS, the reaction mixture was allowed to cool to RT and diluted with water. The resulting precipitate was filtered, and the solid washed with water and diethyl ether. The solid was then taken up in 9:1 CH2Cl2:MeOH and passed through a pad of silica gel with 9:1 CH2Cl2:MeOH as eluent. The solvent was concentrated in vacuo to provide the desired product, 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine. MS m/z=280 [M+1]+. Calc'd for C15H13N5O: 279.30.
Reaction SMILES: [C:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CCOCC>CCOC(C)=O>[C:27]([O:26][C:24](=[O:25])[CH2:23][N:13]1[C:12](=[O:21])[CH2:11][C:10]2[N:16]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]1=2)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2ccccc2N1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 44.3 %

Procedure:
Following the procedure described for Preparation 13(A), 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(A)) (5.0 g, 18.1 mmol) was alkylated with tert-butyl bromoacetate (2.94 mL, 19.9 mmol). Trituration with Et2O (100 mL), hexanes (30 mL) and EtOAc (10 mL) provided 3.13 g of (5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetic acid tert-butyl ester. 1H NMR (CD3OD) δ 7.68 (d, 1H), 7.60-7.51 (m, 4H), 7.43 (m, 2H), 7.23 (t, 1H), 6.99 (d, 1H), 4.86 (d, 1H), 4.44 (d, 1H), 3.99 (d, 1H), 3.83 (d, 1H), 1.36 (s, 9H); MS 391.4 (M+1), 389.3 (M−1).