Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH:11]=O)[N:6]2[N:5]=[CH:4][N:3]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
To a suspension of Intermediate AW (N-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (50 mg, 0.1 mmol)) and morpholine (0.01 ml, 0.12 mmol) in dichloroethane (3 ml) was added sodium triacetoxyborohydride (67 mg, 0.31 mmol). The reaction was stirred under N2 at rt for 16 h. The reaction mixture was diluted with CH2Cl2 and subsequently quenched with aqueous saturated NaHCO3. The organic phase was collected, dried (Na2SO4), concentrated and purified via column chromatography (95:5 v/v CH2Cl2-MeOH) to afford 26 mg of the title compound (yield 46%). 1H-NMR (DMSO-d6) 9.32 (s, 1H), 8.96 (d, J=2 Hz, 1H), 8.64 to 8.61 (dd, J=8, 2 Hz, 1H), 7.90 (s, 1H), 7.59 to 7.34 (m, 6H), 4.29 (s, 2H), 3.86 (s, 2H), 3.55 to 3.50 (m, 4H), 3.14 (s, 3H), 2.47-2.41 (m, 4H); MS [M+H]+=573.9; LCMS RT=2.53 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].Cl[C:39](=[O:44])[C:40]([O:42][CH3:43])=[O:41]>>[CH3:43][O:42][C:40](=[O:41])[C:39]([NH:1][C@H:2]([C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:44]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: COC(=O)C(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (see example 8) as described in general procedure D using methyl chlorooxoacetate. The final product was obtained in 75% yield.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12](F)[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.N12CCCN=C1CCCCC2>C(#N)C>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([N:26]3[CH2:27][C:28]4[CH2:29][NH:30][CH2:31][C:24]=4[CH2:25]3)[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1NCC2=C1CNC2
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4=C(CNC4)C3)c(F)c21
Yield: 91.3 %

Procedure:
1-tert-Butyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.32 g), 3,7-diazabicyclo-[3.3.0] oct-1(5)-ene dihydrobromide (0.3 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 0.55 ml) in acetonitrile (12 ml) was refluxed for 5 hours. The produced precipitate was collected by filtration, washed with acetonitrile and methanol to give the title compound (0.38 g, yield 92%)
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]2[CH2:16][CH:11]1[CH2:12][CH:13]2[OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:19]1[N:20]=[C:21]([N:34]2[CH:39]3[CH2:40][CH2:41][CH:35]2[CH2:36][O:37][CH2:38]3)[C:22]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][S:25][C:23]=2[N:24]=1.CO>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]2[CH2:16][CH:11]1[CH2:12][CH:13]2[O:17][C:19]1[N:20]=[C:21]([N:34]2[CH:35]3[CH2:41][CH2:40][CH:39]2[CH2:38][O:37][CH2:36]3)[C:22]2[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][S:25][C:23]=2[N:24]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CC2O
Reactant: Clc1nc(N2C3CCC2COC3)c2c(-c3ccccc3)csc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC1CC2Oc1nc(N2C3CCC2COC3)c2c(-c3ccccc3)csc2n1
Reaction time: 0.17 h
Yield: 162.2 %

Procedure:
Sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) was added to a solution of 5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.1023 g, 0.4652 mmol) in dry THF (2 mL). The mixture was stirred for 10 min and then a solution of 8-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.111 g, 0.3101 mmol) in dry THF (3 mL) was added. The mixture was stirred overnight at room temperature. A second batch of sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) was added and the mixture was stirred overnight. Further batches of 5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.1023 g, 0.4652 mmol) and sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) were added and the mixture was stirred for 3 nights. It was poured into methanol to quench the reaction, and then the solvent was evaporated. The residue was dissolved in EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (1×10 mL), filtered through a hydrophobic frit and evaporated to give tert-butyl-5-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]oxy-2-azabicyclo[2.2.1]heptane-2-carboxylate as a brown solid (269 mg) which was used in the next step without further purification. LCMS RT=4.23 min. M+1=535.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([CH3:16])=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH3:17])=[N:13]2)=[CH:8][CH:7]=1.[Se](=O)=[O:19]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([CH3:16])=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH:17]=[O:19])=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=[Se]=O
Reactant: COCCOc1ccc2ccc(C)nc2c1C
Solvent: C1COCCO1
Solvent: O
Product: COCCOc1ccc2ccc(C=O)nc2c1C
Yield: 70 %

Procedure:
To 7-(2-methoxyethoxy)-2,8-dimethylquinoline (90 mg, 0.39 mmol) in dioxane/water (5 mL/0.5 mL) at ambient temperature was added selenium dioxide (52 mg, 0.47 mmol) and the reaction was heated to reflux for 1 hour. After cooling, the reaction was filtered and the solids washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-(2-methoxyethoxy)-8-methylquinoline-2-carbaldehyde (67 mg, 70% yield) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:13][C:14]1[C:15](=[O:25])[C:16](=O)[C:17]=1[NH:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH3:21])C>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:16]1[C:15](=[O:25])[C:14](=[O:13])[C:17]=1[NH:18][C:19]([CH3:22])([CH3:23])[CH2:20][CH3:21]
Reactant: NCc1ccc(F)cc1Cl
Reactant: CCOc1c(NC(C)(C)CC)c(=O)c1=O
Solvent: CC#N
Product: CCC(C)(C)Nc1c(NCc2ccc(F)cc2Cl)c(=O)c1=O

Procedure:
This compound was prepared according to the procedure for Example 59. From 2-chloro-4-fluorobenzylamine and 3-ethoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione in acetonitrile. The title compound was obtained, after recrystallization from petroleum ether, as a white solid (60%); mp 201°-203° C.; 1H NMR (DMSO-d6) δ0.81 (t, 3H), 1.30 (s, 6H), 1.68 (q, 2H), 4.76 (d, 2H), 7.25 (m, 1H), 7.50 (m, 3H), 7.78 (m, 1H) ppm; IR (KBr) 3250, 3040, 1790, 1660, 1580, 1530, 1490 cm-1 ; MS (m/z) 325 ([M+H]+).
Reaction SMILES: [ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:28]1C2C=CC3C(=CC(C=O)=C4C=3C=CC=C4)C=2C=CC=1.NC(CC)(CO)CO>CCO.CCOCC>[ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH2:27][CH3:28])([CH2:23][OH:24])[CH2:25][OH:26])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: CCC(N)(CO)CO
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12

Procedure:
Using the reductive amination procedure described in 1B, 6-chrysenecarbaldehyde (1A) and 2-amino-2-ethyl-1,3-propanediol (Aldrich) gave 2-((6-chrysenylmethyl)amino)-2-ethyl-1,3-propanediol hydrochloride, mp 241°-243° (dec), (EtOH/Et2O), (C, H, Cl, N).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C[Si](C)(C)[N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1>C1CCCCC1.O1CCCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:13]2[CH2:14][CH2:15][NH:11][C:12]2=[O:16])=[CH:22][N:21]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: ClCc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C1NCCC1Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere at a temperature of from −78° C. to −60° C., 180 ml of a 1.5 molar solution of lithium diisopropylamide (LDA) in cyclohexane are added dropwise to 31.4 g of N-trimethylsilylpyrrolid-2-one in 150 ml of tetrahydrofuran (THF) and the reaction mixture is stirred at the same temperature for a further one hour. Then, at from −78° C. to −60° C., 25.5 g of 2-chloro-5-chloromethylpyridine in 40 ml of THF are added, and the mixture is stirred for a further 16 hours at that temperature and then for a further three hours at room temperature. The reaction mixture is poured onto a mixture of ice/water and extracted with ethyl acetate, and the organic phase is separated off. The ethyl acetate phase is dried over sodium sulfate and concentrated to dryness by evaporation in vacuo. The residue is purified on silica gel using ethyl acetate/hexane (7:1) as eluant. The title compound having a melting point of 117-118° C. (compound 1.3) is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][O:20][CH3:21].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:18][CH2:19][O:20][CH3:21])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(C)=O)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (03.070; 2.00 g) and 1-bromo-2-methoxyethane (1.5 g) were dissolved in DMF (20 ml), and sodium hydride (259 mg) was added. After stirring at RT for 3 h, the mixture was left to stand overnight. Then the DMF was drawn off and the residue was taken up in EA. The EA phase was washed with water, dried, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA 0-40% within 60 min). 1.17 g of the title compound were obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[N:17]1[O:18][N:19]=[C:20]2[CH:25]=[C:24]([C:26](Cl)=[O:27])[CH:23]=[CH:22][C:21]=12>ClCCl>[CH3:1][N:2]([CH2:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:26]([C:24]1[CH:23]=[CH:22][C:21]2=[N:17][O:18][N:19]=[C:20]2[CH:25]=1)=[O:27]
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: CNCC1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC1CCOCC1)C(=O)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl tetrahydro-2H-pyran-4-carboxylate (5 ml, 40.0 mmol) was added to a solution of methylamine (generated by heating a mixture of methylamine hydrochloride and sodium hydroxide pellets) in THF (30 ml) and the mixture heated at 110° C. in a bomb reactor overnight. The solvents were evaporated, the residue dissolved in THF (100 ml), and LiAlH4 (4.6 g, 121 mmol) added, and the mixture heated at 70° C. for 1 h. The mixture was cooled to 0° C., concentrated NaOH solution added and the THF evaporated. Chloroform (100 ml) was added to the residue and the resulting solid was filtered off and the filtrate concentrated under vacuum to give N-methyl-N-tetrahydro-2H-pyran-4-ylmethylamine as a pale brown oil. The preceding amine (1 g, 7.8 mmol) was dissolved in dichloromethane (50 ml), and triethylamine (4 ml) and [2,1,3]-benzoxadiazole-5-carbonylchloride (1.7 g, 9.3 mmol), as a solution in dichloromethane (20 ml), were added, slowly. The mixture was stirred at room temperature for 1 h, the mixture washed with 1N HCl (20 ml), and saturated sodium bicarbonate solution (20 ml), dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate/chloroform (3:1) to give the title compound as a pale brown oil. 1H NMR (300 MHz, CDCl3, 2-rotamers) δ 7.93 (d, J=9.3 Hz, 1H), 7.83 (br s, 1H), 7.38-7.45 (m, 1H), 4.10-3.90 (m, 2H), 3.52-3.20 (m, 4H), 3.13 and 3.05 (both s, total 3H), 2.18-1.80 (m, 1H), 1.73-1.40 ppm (m, 4H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:19][C:18](=[O:20])[NH:17][CH:16]=C2C(O)=O)=[CH:10][CH:9]=1>ClCCl.CN(C=O)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[CH2:19][C:18](=[O:20])[NH:17][CH:16]=[C:1]2[C:2]([Cl:4])=[O:3])=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)O)=CN1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)Cl)=CN1
Reaction time: 0.5 h

Procedure:
Oxalylchloride (0.91 g 7.2 mmol) was added to a room temperature solution of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid (1.124 g, 4.8 mmol) in dichloromethane (10 ml) containing 2 drops of DMF. The reaction mixture was stirred for 30 minutes and then solvent was removed under reduced pressure to give crude (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride, which was not removed from the flask. Dichloromethane (10 mL) was added, and the dichloromethane solution of the acid chloride was added to a stirring solution of 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine (1.51 g, 4.7 mmol) and triethyl amine (0.97 g) in dichloromethane (30 ml). The reaction was stirred at 0° C. for 10 minutes, then at ambient temperature for 20 minutes. Solvent was removed under reduced pressure and the residue was purified by flash chromatography (0 to 5% methanol in dichloromethane) to 1.776 g of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-amide as a yellowish solid (69.5% yield).
Reaction SMILES: C1COCC1.[BH4-].[Na+].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][CH:12]=1)([O-])=O>CO.[Ni](Br)Br>[NH2:8][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(CNc2ccccn2)cc1
Agent: Br[Ni]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(CNc2ccccn2)cc1
Yield: 46.1 %

Procedure:
To a solution of nickel bromide (44 mg) in methanol (4 ml)/THF (4 ml) was added sodium boro hydride (40 mg), and the mixture was stirred. To the mixture was added 2-[(4-nitrophenyl)methylamino]pyridine (0.92 g) and then sodium boro hydride (414 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added nickel bromide (44 mg)and sodium boro hydride (454 mg), and the mixture was stirred at room temperature for 2 hours. Insoluble materials were filtered off with sellaite, and to the filtrate was added sodium bicarbonate solution. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried (anhydrous magnesium sulfate) and concentrated, and the residue was purified twice with silica gel column chromatography (ethyl acetate/hexane=1/1) to give 2-[(4-aminophenyl)methylamino]pyridine (369 mg) as pale red solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1.C([Li])CCC.[Si:18]([O:25][C@@H:26]([CH3:34])[C:27](N1CCCC1)=[O:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][C@@H:26]([CH3:34])[C:27]([C:3]1[CH:2]=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[C:4]=1[F:12])=[O:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)N1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)c1cccc(C(F)(F)F)c1F

Procedure:
To a solution of 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (4.93 g, 20.3 mmol) in THF (50 mL) cooled to −78° C. was added slowly over 10 min butyl lithium (8.11 mL, 20.3 mmol, 2.5 M in hexanes). The reaction was transferred via cannula to a cooled solution (−78° C.) of 110 (4.35 g, 16.9 mmol) in THF (50 mL). The reaction was stirred for 10 min after all aryl lithium was added. The reaction was quenched with H2O and extracted with DCM. The organic layer was concentrated and the resulting residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (1 to 5% EtOAc) to afford impure (S)-2-(tert-butyldimethylsilyloxy)-1-(2-fluoro-3-(trifluoromethyl)phenyl)propan-1-one (112) which was used without further purification.
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Na+].[Br:34]N1C(=O)CCC1=O>O>[C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][C:16]([Br:34])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Br)(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a cold solution of a compound of formula IV, preferably 2-benzoyl-[3,3-di(ethoxycarbonyl)propyl]pyrrole, in an aprotic polar solvent, such as tetrahydrofuran, is added a slight excess of a strong base, preferably sodium hydride. The reaction mixture is allowed to stir for about 30 minutes. To the reaction mixture is then added a halogenating agent, preferably N-bromosuccinimide. The reaction mixture is allowed to stir until complete The mixture is poured into water and extracted with an aprotic polar solvent, such as diethyl ether. The organic layers are combined, washed with water and brine, dried, and concentrated under reduced pressure. The residue may be purified by conventional means to produce a compound of formula VII, preferably 2-benzoyl-[3-bromo-3,3-di(ethoxycarbonyl)propyl]pyrrole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].OS(O)(=O)=O.[CH2:23](O)[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH2:23][CH3:24])=[O:9]
Reactant: O=C(O)c1ccccc1Oc1cccc(F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1Oc1cccc(F)c1

Procedure:
2-(3-Fluorophenoxy)benzoic acid (10 g.) and 100 ml of ethanol containing 1 ml. of concentrated H2SO4 were heated at reflux through molecular sieves overnight. The solvent was evaporated, and the residue poured into 50 ml. of 7% NaHCO3. The resulting ester was extracted with ether. ##STR10##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.O>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
5-Aminoindole (100 mg, 0.757 mmol) was dissolved in DMF (2 mL), and the solution was added with EDCI (290 mg, 1.51 mmol), HOBT monohydrate (102 mg, 0.755 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (208 mg, 0.907 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using acetonitrile to obtain 5-[1-(tert-butoxycarbonyl)piperidine-4-carbonylamino]indole (142 mg, yield 55%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.C[C:24]#[N:25].O>CN(C)C=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:16]1[C:12]2([CH2:17][CH2:18][CH:9]([O:8][C:6]3[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=[C:2]([C:24]#[N:25])[CH:7]=3)[CH2:10][CH2:11]2)[O:13][CH2:14][CH2:15]1
Reactant: CC#N
Reactant: FC(F)(F)c1nc(Cl)cc(OC2CCC3(CC2)OCCO3)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 140 °C

Procedure:
4-Chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine (described in Example 1, Step 1) (27.1 mg, 0.0800 mmol) was stirred in N,N-dimethylformamide (1.3 mL). Zinc cyanide (23 mg, 0.20 mmol) was adde, followed by tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0096 mmol). The solution was flushed with nitrogen (subsurface). The vial was sealed, and the solution was heated at 140° C. for 10 minutes in a microwave reactor. LCMS showed no remaining starting material and showed a new peak that did not ionize. The product was isolated by preparative LC using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column; 62% CH3CN—H2O (0.1% TFA), 0.5 min, 4.5 min gradient to 82%; 60 mL/min; detector set at 254 nm; retention time=3.8 min. The solvent was removed by rotary evaporation to give 21 mg. 1H NMR (400 MHz, acetone-d6): δ 7.78 (s, 1H); 5.41 (m, 1H, OCH); 3.94 (s, 4H, OCH2); 1.9-2.1 (m, 4H); 1.83 (m, 2H); 1.67 (m, 2H). 13C NMR (100 MHz, acetone-d6): δ 171.6 (s, OC); 142.1 (s, C—N); 117.8 (s, CH); 115.8 (s, CN); 108.2 (s, O2C); 76.1 (s, OCH); 65.0 (s, OCH2); 31.7 (s, CH2); 28.6 (s, CH2); two quartets were not resolved due to insufficient number of scans. The compound of Example 54 was then obtained by following the steps described for Example 45.