Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@H:10]([O:11][C:12]([O:14][CH3:15])=[O:13])[C@@H:9]([CH3:16])[O:8][C@H:7]1[N:17]1[CH:24]=[C:23]([F:25])[C:21]([NH2:22])=[N:20][C:18]1=[O:19])=[O:4].N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:34].Cl>ClCCl>[CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@H:10]([O:11][C:12]([O:14][CH3:15])=[O:13])[C@@H:9]([CH3:16])[O:8][C@H:7]1[N:17]1[CH:24]=[C:23]([F:25])[C:21]([NH:22][C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:34])=[N:20][C:18]1=[O:19])=[O:4]
Reactant: COC(=O)O[C@@H]1[C@H](OC(=O)OC)[C@@H](C)O[C@H]1n1cc(F)c(N)nc1=O
Reactant: CCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](OC(=O)OC)[C@H]2OC(=O)OC)cc1F
Temperature: -2.5 °C
Yield: 91.1 %

Procedure:
35.8 g (0.099 mole) of the compound obtained in Example 2 was mixed with 163 ml of dichloromethane and 11 ml (0.136 mole) of pyridine, and stirred. After cooling the resulting mixture to −5 to 0° C., 15.7 ml (0.109 mole) of n-pentyl chloroformate was added dropwise thereto while maintaining the temperature of the reaction mixture at less than 0° C., followed adding the resulting mixture was warmed to room temperature and stirred for 2 hrs, 1 N HCl thereto. The organic layer was separated, successively washed with 163 ml of saturated sodium bicarbonate and 163 ml of water, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure, to obtain 42.9 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:12][CH:13]=[CH:14][C:5]=3[C:4](=[O:15])[N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]3[CH:26]=[CH:27][C:28]([C:30]([OH:32])=[O:31])=[CH:29][C:22]=3[S:21]1(=[O:34])=[O:33])[CH:8]=[CH:9][CH:10]=2.[OH-:35].[Na+].Cl>C(O)C>[O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:12][CH:13]=[CH:14][C:5]=3[C:4](=[O:15])[N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:22]1[CH:29]=[C:28]([C:30]([OH:32])=[O:31])[CH:27]=[CH:26][C:23]=1[C:24]([OH:35])=[O:25])(=[O:34])=[O:33])[CH:8]=[CH:9][CH:10]=2
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)N(CCCCN1C(=O)c3cccc4cccc(c34)C1=O)C2=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(C(=O)O)c(S(=O)(=O)NCCCCN2C(=O)c3cccc4cccc(c34)C2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 9 (50 mg) and aqueous 1N NaOH (3 mL) was stirred at room temperature for 10 min. To this suspension, ethanol (2 mL) was added until the solution became clear. Stirring was continued for 2 h until starting material was disappeared. The solution was poured into ice-water and acidified with 37% HCl to a pH of 1. The resulted mass was extracted with ethylacetate, the organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under vacuum to get the crude product. The crude residue was recrystallized using EtOAc-Hexane-DCM to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.5 (bs, 1H), 9.30 (bs, 1H), 8.58-8.35 (m, 4H), 8.05 (d, J=8.0 Hz, 1H), 7.99-7.86 (m, 2H), 7.65-7.52 (m, 2H), 4.01-3.97 (m, 2H), 3.50-3.40 (m, 2H), 1.52-1.40 (m, 4H). MS (ES−) m/z 495 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:15][CH2:16][CH3:17])=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH4+].[Cl-].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:38]([O:40][C:41](=[O:53])[C:42]([O:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1)([CH3:44])[CH3:43])[CH3:39]>C(Cl)Cl.CN(C=O)C>[CH2:38]([O:40][C:41](=[O:53])[C:42]([CH3:44])([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[CH2:15][CH2:16][CH3:17])=[CH:48][CH:47]=1)[CH3:43])[CH3:39]
Reactant: CCCc1oc(-c2ccccc2)nc1CCO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1oc(-c2ccccc2)nc1CCOc1ccc(OC(C)(C)C(=O)OCC)cc1
Reaction time: 1 h
Yield: 46 %

Procedure:
2-(2-Phenyl-5-propyloxazol-4-yl)ethanol (225 mg, 0.97 mmol) and triethyl amine (167 mg, 1.65 mmol, 0.23 mL) were dissolved in CH2Cl2 (3.5 mL) at 0° C. and treated with methane sulfonyl chloride (167 mg, 1.46 mmol, 0.11 mL). After 1 h, NH4Cl (25 mL of a 10% aqueous solution) was added and then the organic phase was dried (MgSO4), filtered and concentrated to an oil. The intermediate mesylate was combined with Cs2CO3 (383 mg, 1.18 mmol), and 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691) (190 mg, 0.84 mmol) in DMF (4 mL) and heated to 55° C. After 18 h, the reaction mixture was partitioned between H2O (25 mL) and EtOAc (25 mL) and then the organic phase washed with H2O (2×), dried (MgSO4), filtered and concentrated. The product was purified by flash chromatography (70 mL SiO2, hexanes to 20% EtOAc/hexanes) and obtained as a colorless oil (170 mg, 46%): Rf=0.49 in 20% EtOAc/hexanes; 1H NMR (500 MHz, CDCl3) δ 8.00-7.96 (m, 2H), 7.42-7.38 (m, 3H), 6.83-6.76 (m, 4H), 4.22 (q, J=7.0 MHz, 2H), 4.19 (t, J=7.0 Hz, 2H), 2.95 (t, J=7.0 Hz, 2H), 2.67 (t, J=7.0 Hz, 2H) 1.71 (sextet, J=7.0 Hz, 2H), 1.52 (s, 6H), 1.26 (t, J=7.0 Hz, 3H), 0.96 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>>[C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[O:16])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)O
Reactant: Nc1ccc2[nH]ccc2c1
Product: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example 75(c), (0.88 g, 4.0 mmol) and 5-aminoindole (0.53 g, 4.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 334 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[OH:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH:20]([C:22]1[C:34]([CH3:35])=[CH:33][C:25]([O:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][C:23]=1[CH3:36])=O>CO>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:16]=[CH:17][C:18]3[O:19][C:20]([C:22]4[C:23]([CH3:36])=[CH:24][C:25]([O:26][CH2:27][C:28](=[O:29])[N:30]([CH3:31])[CH3:32])=[CH:33][C:34]=4[CH3:35])=[N:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1cc(OCC(=O)N(C)C)cc(C)c1C=O
Reactant: Cc1ccc(NC(=O)c2ccc(O)c(N)c2)cc1C
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3oc(-c4c(C)cc(OCC(=O)N(C)C)cc4C)nc3c2)cc1C
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A mixture of 3-amino-N-(3,4-dimethylphenyl)-4-hydroxy-benzamide (70 mg) and 2-(4-formyl-3,5-dimethylphenoxy)-N,N-dimethylacetamide (64 mg) in MeOH (5 mL) was stirred at 45° C. for 24 h. The MeOH was removed under reduced pressure and the residue was dissolved in CH2Cl2 (5 mL). To this solution was added DDQ (68 mg) and the dark mixture was stirred at room temperature for 6 h. The majority of the solvent was removed under reduced pressure and EtOAc was added. The solution was washed with NaHCO3 solution and water then was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using EtOAc/CH2Cl2 (1:2) as eluent to give 2-(4-dimethylcarbamoylmethoxy-2,6-dimethylphenyl)-benzooxazole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a brownish solid, mp=207-209° C.; MS (m/z) 470 (M−1); 1H NMR (DMSO-d6, 400 MHz) δ 10.18 (s, 1H), 8.46 (s, 1H), 8.04 (d, J=10.36 Hz, 1H), 7.90 (d, J=8.34 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J=8.08 Hz, 1H), 7.11 (d, J=8.34 Hz, 1H), 6.83 (s, 2H), 4.89 (s, 2H), 3.02 (s, 3H), 2.87 (s, 3H), 2.27 (s, 6H), 2.24 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 4-ethylaniline (2 g) and triethylamine (13.91 mL) in dichloromethane (40 mL) at 0° C. under nitrogen was treated dropwise with acetic anhydride (4.67 mL). The mixture was warmed to ambient temperature, then stirred for 16 hours at room temperature, then washed with (i) 10% citric acid (40 mL), (ii) water (40 mL) and (iii) brine (40 mL). The organic phase was dried over magnesium sulfate and then evaporated to give 4-ethyl-N-acetyl-aniline (2.36 g) as a pale orange solid which was used without further purification. LC-MS (METHOD B): RT=2.80 minutes; 164.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[C:18](F)[CH:17]=[C:16]([NH:21][C:22]3[CH:27]=[C:26]([C:28](=[O:31])[NH:29][CH3:30])[CH:25]=[CH:24][C:23]=3[CH3:32])[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[C:18]([N:35]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:34])[CH:17]=[C:16]([NH:21][C:22]3[CH:27]=[C:26]([C:28](=[O:31])[NH:29][CH3:30])[CH:25]=[CH:24][C:23]=3[CH3:32])[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)(C)C
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(F)nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(R)-[4-fluoro-6-(2-methyl-5-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.36 g, 0.81 mmol), N-methyl-neopentylamine hydrochloride (411 mg, 3 mmol) and DIEA(0.4 mL) in 1,4-dioxane (0.5 mL) was stirred at 90° C. overnight. After removing the solvent under reduced pressure the desired product (81 mg) was purified by silica gel chromatography. C28H43N7O3 MS m/e=526 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[OH:18][C:19]1([C:25]#[C:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[CH:26][C:25]([C:19]3([OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(=O)C#CC2(O)CCCCC2)cc1
Reactant: COc1ccc(NN)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C3(O)CCCCC3)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a suspension of 4-methoxyphenylhydrazine (165 mg, 0.944 mmol) in ethanol (5.0 mL), triethylamine (258 μL, 1.88 mmol) was added, and the obtained solution was stirred at room temperature for 30 minutes. The resulting solution was added to a solution of 3-(1-hydroxycyclohexyl)-1-(4-tolyl)-2-propyn-1-one (Reference Example 14) (214 mg, 0.883 mmol) in ethanol (3.0 mL), and the resulting mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and distilled water was added to the residue. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (141 mg, 0.389 mmol, 44%) as a yellow amorphous product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([CH:8]([CH2:14][CH:15]2[CH2:16][CH2:17]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Br:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(CC1CC1)c1ccc(N)c(OCC(F)(F)F)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC1CC1)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.1 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9 g, 2.7 mmol) in dry CHCl3 (50 mL), NBS (0.412 g, 2.3 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.02 g) as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([BH-](CC)CC)C.[Li+]>C1COCC1.C([O-])(O)=O.[Na+].O>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH3:21])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)cc1
Agent: CC[BH-](CC)CC
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-({[(4-methylphenyl)-sulfonyl]-oxy}methyl)pyrrolidine-1-carboxylate (6.32 g, 13.01 mmol) was dissolved in THF (50 mL) under nitrogen and cooled to 0° C. Lithium triethylborohydride solution (Super Hydride, 14.3 mL, 1.0 M in THF) was added dropwise and the mixture was then slowly warmed to room temperature. After 2 hours, TLC revealed half conversion. More lithium triethylborohydride solution (12.0 mL) was added and the solution stirred at room temperature overnight. Diluted with NaHCO3/H2O and extracted twice with ethyl acetate. Washed organic layer with NH4Cl/H2O and brine. Dried organic extracts over MgSO4, filtered and concentrated to give a colorless oil. Chromatographed on silica gel eluting with 10% ethyl acetate/hexane. Pure fractions were combined to give the desired product as a colorless oil, 3.74 g (91%). LC/MS (M+Na)+ m/z=338.2. 1H NMR (CDCl3) δ 4.34 (m, 1H), 3.95 (m, 1H), 3.35 (m, 2H), 1.98 (m, 1H), 1.65 (m, 1H), 1.47 (s, 9H), 1.20 (bs, 3H), 0.87 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: ClCCl.[N+:4]([C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][O:12][C:13]2=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5].[Br:17]Br.OO>O>[N+:4]([C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([Br:17])[O:12][C:13]2=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Reactant: BrBr
Agent: OO
Solvent: O
Solvent: ClCCl
Product: O=C1OC(Br)c2ccc([N+](=O)[O-])cc21

Procedure:
To 125 ml of a dichloromethane solution of 6-nitrophtalide (8.0 g, 0.047 mol), bromine (8.25 g, 0.052 mol, 1.15 eq) and hydrogen peroxide (5.07 g of a 35% solution in water, equivalent to 1.77 of hydrogen peroxide, 0.052 mol, 1.15 eq) were added. The mixture was gently refluxed for 11 hours, then cooled down and concentrated by solvent evaporation. The aqueous layer was separated, and the organic phase washed with water before drying up (Na2SO4).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][C:12]([F:21])=[CH:11][C:10]=2[F:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26][CH2:27][N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[C:36]([NH2:39])[CH:37]=[CH:38][C:31]=2[CH2:30][CH2:29]1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][C:12]([F:21])=[CH:11][C:10]=2[F:22])=[N:7][C:2]([NH:39][C:36]2[CH:37]=[CH:38][C:31]3[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][O:25][CH3:24])[CH2:34][CH2:33][C:32]=3[CH:35]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Fc1cc(F)c(Nc2nc(Cl)ncc2Cl)c(N2CCOCC2)c1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cc(F)cc4N4CCOCC4)n3)cc2CC1

Procedure:
Title compound was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2,4-difluoro-6-morpholin-4-yl-phenyl)-amine and 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (80 mg, 48%), HPLC 99% purity, LCMS 547.26 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.69 (s, 1H), 9.37 (s, 1H), 8.52 (s, 1H), 8.13 (s, 1H), 7.28 (s, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.02 (dd, J=6.9 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.83 (10.9 Hz, 1H), 3.70-3.68 (m, 2H), 3.62-3.58 (m, 2H), 3.55-3.50 (m, 4H), 3.37-3.35 (m, 2H), 3.33 (s, 3H), 3.15-2.87 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][C:26]#[N:27])[C:5]2=3)[CH:14]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH2:27])[C:5]2=3)[CH:14]=1
Reactant: Cc1cc2c3c(c1)c1c(OCC#N)cccc1n3C(c1ccccc1)CO2
Solvent: C1CCOC1
Product: Cc1cc2c3c(c1)c1c(OCCN)cccc1n3C(c1ccccc1)CO2
Temperature: 85 °C
Yield: 66.6 %

Procedure:
To a mixture of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile (0.66 g, 1.86 mmol) in dry THF (120 mL) is added borane-methylsulfide complex (0.53 mL, 5.6 mmol). The mixture is refluxed at 85° C. for 18 h. The mixture is removed from heat and methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added and again removed. The residue is dissolved in CH2Cl2/CH3OH (1:2 15 mL). Conc. HCl (2 mL) is added and the mixture heated at 65° C. for 1 h. The mixture is removed from heat and neutralized with aqueous potassium carbonate then partitioned between water and CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. Column chromatography (70 g silica gel) using CH3OH/CH2C2 (4:96) as eluent gave 0.444 g (67%) of the title compound;
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16]>>[Cl:11][CH2:12][C:13]1[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]2[C:15](=[O:16])[CH:14]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1nc(C(F)(F)F)cs1
Product: O=c1cc(CCl)nc2scc(C(F)(F)F)n12

Procedure:
This compound was synthesized from 2-amino-4-trifluoromethylthiazole, Step 1 intermediate (3.70 g, 22.541 mmol) and ethyl chloroacetoacetate (5.194 g, 31.558 mmol) in polyphosphoric acid (30.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 4.0 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.60 (s, 3H), 4.52 (s, 1H), 6.25 (s, 1H); ESI-MS (m/z) 269.22 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]=[C:13]1[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]1=[O:22])=[CH:6][NH:7]2.[CH:23]1([Mg]Br)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[Cl-].[NH4+].Cl>C1COCC1>[CH:23]1([CH:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1])[NH:7][CH:6]=2)[CH:13]2[C:18](=[O:19])[O:17][C:16]([CH3:20])([CH3:21])[O:15][C:14]2=[O:22])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1cccc2[nH]cc(C=C3C(=O)OC(C)(C)OC3=O)c12
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc2[nH]cc(C(C3CCCCC3)C3C(=O)OC(C)(C)OC3=O)c12

Procedure:
5-(4-Methoxy-1H-indol-3-ylmethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (0.392 g) was dissolved in dry THF (15 ml) and added slowly to cyclohexyl-magnesium bromide (10 ml, 1M) at room temperature with stirring. The reaction was stirred for 20 minutes, and then was worked up by the careful addition of saturated ammonium chloride solution, acidified with dilute HCl, and extracted with ethyl acetate. The crude product was purified on silica gel. Elution was done with 3:7 ethyl acetate-hexane to afford 0.390 g of 5-[cyclohexyl-(4-methoxy-1H-indol-3-yl)-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH2:11])=[N:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O.[CH2:19]([N:26]([CH2:32]OC)[CH2:27][Si](C)(C)C)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH2:19]([N:26]1[CH2:32][CH2:11][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccc([N+](=O)[O-])cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(C2CCN(Cc3ccccc3)C2)nc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
0.15 g of 5-nitro-2-vinyl-pyridine were dissolved in 2.5 ml of dichloromethane, 0.149 g of trifluoroacetic acid (1.31 mmol) were added, followed by slow addition of 0.928 g of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (3.91 mmol). Stirring was continued at room temperature for 1 h, before the reaction mixture was washed with aqueous sodium hydrogencarbonate, the aqueous layer reextracted with dichloromethane, the organic layers combined, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with ethyl acetate. Fractions containing the product were combined, the solvent evaporated to yield 0.186 g of the desired product.
Reaction SMILES: CN(C)C1C=CC=CC=1.Cl[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12].[Br:26][C:27]1[CH:36]=[C:35]([CH3:37])[C:34]([CH3:38])=[CH:33][C:28]=1[NH:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[Br:26][C:27]1[CH:36]=[C:35]([CH3:37])[C:34]([CH3:38])=[CH:33][C:28]=1[N:29]([CH:30]([CH3:32])[CH3:31])[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Cc1cc(Br)c(NC(C)C)cc1C
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Br)c(N(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C(C)C)cc1C
Temperature: 25 °C

Procedure:
N,N-dimethylaniline (7.12 mL, 56.2 mmol) followed by tert-butyl 4-(chlorocarbonyl)piperidine-1-carboxylate 1-11 (42.1 mL of a 1 M solution in methylene chloride, 42.1 mmol) were added to a neat stirred mixture of 2-bromo-N-isopropyl-4,5-dimethylaniline 1-9 (6.80 g, 28.1 mmol) and N,N-dimethylamino-pyridine (172 mg, 1.40 mmol) at approximately 0° C. The resulting mixture was heated to reflux for 30 min, cooled to ambient temperature and partitioned between diethyl ether and aqueous 1 N hydrochloric acid. The organic phase was separated and washed successively with aqueous 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-40% ethyl acetate/hexanes as eluent) afforded 1-12 as a white solid.