Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2C=CC=C(Cl)C=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.IC1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Reactant: Cc1csc(I)n1
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCN)n1

Procedure:
The title compound was prepared analogously to Intermediate B by replacing 1-bromo-3-chlorobenzene with 2-iodo-4-methylthiazole (Intermediate F)
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH3:5].[CH2:7]([O:14][C:15]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([C:28](=[S:30])[NH2:29])[N:17]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:16]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCO>[CH2:7]([O:14][C:15]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([C:28]2[S:30][CH:2]=[C:3]([CH2:4][CH3:5])[N:29]=2)[N:17]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:16]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(N)=S)n1-c1ccc(OC)cc1
Reactant: CCC(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2nc(CC)cs2)n1-c1ccc(OC)cc1
Yield: 75.9 %

Procedure:
A solution of 1-bromobutan-2-one (24 μL, 0.21 mmol) and ethyl 3,4-bis(benzyloxy)-5-carbamothioyl-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (29) [prepared under standard conditions from UL1-079 and Lawesson reagent] (100 mg, 0.19 mmol) in EtOH (4 mL) was heated at 80° C. for 45 min. The volatiles were removed in vacuo and the product was purified by silica gel chromatography (12 g cartridge, 0-25% EtOAc in isohexane) to afford ethyl 3,4-bis(benzyloxy)-5-(4-ethylthiazol-2-yl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (30) (82 mg, 75%) as a yellow oil: m/z 569 (M+H)+ (ES+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH3:22][C:23]([CH3:25])=[O:24]>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:23]([OH:24])([CH3:25])[CH3:22])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: COC(=O)c1nc2n(c1C(C)(C)O)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (0.3 g) was reacted with Acetone similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-9-fluoro-3-(2-hydroxypropan-2-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate was reacted via General Procedure L to provide 10-bromo-9-fluoro-3-(2-hydroxypropan-2-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted as a crude with 2-Methyl-3-butyne-ol via General Procedure E to afford 23 mg (7%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(1-hydroxy-1-methyl-ethyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=398.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([Sn](C)(C)C)=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.Br[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>CN(C=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1
Reactant: Brc1ccncc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CSc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
2-Methylthio-4-[5-trimethylstannyl-benzimidazol-1-yl]pyrimidine (150 mg), 4-bromopyridine (180 mg), tri-o-tolylphosphine (5 mg) and tris(dibenzylidineacetone)dipalladium(0) (7.5 mg) were dissolved in DMF (3 mL) and heated to 100° C. for 1 hour. Upon cooling to rn and evaporation of solvent, the reaction residue was directly purified by column chromatography (SiO2,5% MeOH in CH2Cl2) to yield 100 mg of the title compound. Mass spectrum (ESI) 320.2 (M+1).
Reaction SMILES: CN(C)CCCN=C=NCC.[ClH:12].Cl.Cl.[CH3:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH2:19][C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]#[C:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2([CH3:37])[CH3:36])[CH2:21]1.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1)[C:47](O)=[O:48].ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[ClH:12].[ClH:12].[F:42][C:43]([F:57])([F:58])[C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:54])[F:55])[CH:52]=1)[C:47]([N:25]1[CH2:24][CH2:23][N:22]([CH2:26][C:27]#[C:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2([CH3:37])[CH3:36])[CH2:21][C@H:20]1[CH2:19][C:18]1[CH:38]=[CH:39][C:40]([CH3:41])=[C:16]([CH3:15])[CH:17]=1)=[O:48]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3(C)C)CCN2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 153486.91 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.22 ml) was added over 5 minutes to a mixture of (3R)-3-(3,4-dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine trihydrochloride (0.48 g) and 3,5-bis(trifluoromethyl)benzoic acid (0.27 g), 1-hydroxybenzotriazole (0.15 g) and triethylamine (0.35 ml) in dichloromethane (10 ml). After 2 hours of stirring at room temperature, the reaction mixture was directly purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound was collected and evaporated under reduced pressure. The residue was treated with 4N hydrogen chloride in ethyl acetate and recrystallized from a mixture of acetone and water to give colorless crystals of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine dihydrochloride (525 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.C([O-])(=O)C.[Na+].[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([O:11][CH2:12][CH3:13])=[C:4]([F:14])[C:3]=1[Br:20]
Reactant: CCOc1cc(Br)cc(F)c1OCC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(Br)c(Br)c(F)c1OCC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
To a solution of 5-bromo-1,2-diethoxy-3-fluorobenzene (40.0 g, 0.15 mol) in acetic acid (200 mL), sodium acetate (16.2 g, 0.20 mol) and bromine (31.6 g, 0.20 mol) were added sequentially at room temperature, and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium thiosulfate (400 mL) and water (400 mL) were added sequentially. The mixture was extracted once with heptane (800 mL) and three times with heptane (400 mL). The organic layer was washed sequentially with water (400 mL), once with a 2 N aqueous solution of sodium hydroxide (200 mL), once with a 2 N aqueous solution of sodium hydroxide (100 mL), and water (400 mL), then dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer under reduced pressure and the residue was filtered. The filtrate was then purified by silica gel column chromatography (hexane, ethyl acetate) to give 52.0 g of the title compound (yield:quant.).
Reaction SMILES: [CH3:1][C:2]1[C:11]([F:12])=[C:10](F)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:14])[C:3]=1[F:15].[CH3:16][O-:17].[Na+].[Na]>CO>[CH3:16][O:17][C:10]1[C:11]([F:12])=[C:2]([CH3:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1c(F)c(F)c(C)c(F)c1F
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1c(F)c(F)c(C)c(F)c1OC

Procedure:
Methyl 4-methyl-2,3,5,6-tetrafluorobenzoate (1.0 g) was added to a solution of sodium methoxide obtained by dissolving sodium metal (0.15 g) in dry methanol (15 cm3) and the mixture heated at the reflux temperature for 2 hours until the reaction was complete. The product was purified by h.p.l.c. (Gilson) using a silica column and as eluent a mixture of petroleum ether (boiling range 40°-60° C., 1800 cm3) and diethyl ether (200 cm3), to obtain methyl 2-methoxy-4-methyl-3,5,6-trifluorobenzoate (0.38 g).
Reaction SMILES: [Li]CCCC.[Si:6]([O:13][CH2:14][CH2:15][CH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:22][O:23][C:24]([C:26]1[CH:27]2[N:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:31]([CH2:32][C:33]=1OS(C(F)(F)F)(=O)=O)[CH2:30][N:29]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:28]2)=[O:25]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:22][O:23][C:24]([C:26]1[CH:27]2[N:42]([C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])[CH:31]([CH2:32][C:33]=1[C:19]1[S:18][C:17]([CH2:16][CH2:15][CH2:14][O:13][Si:6]([C:9]([CH3:12])([CH3:10])[CH3:11])([CH3:7])[CH3:8])=[N:21][CH:20]=1)[CH2:30][N:29]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:28]2)=[O:25]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1nccs1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2cnc(CCCO[Si](C)(C)C(C)(C)C)s2)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
BuLi (1.6 M in hexane, 5.7 mL, 9.1 mmol) was added dropwise to a sol. of 2-[3-(tert-butyldimethylsilanyloxy)propyl]thiazole (1.80 g, 6.79 mmol) in THF (15 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, and ZnCl2 (1M in THF, 11.3 mL, 11.3 mmol) was added dropwise at −78° C. The cooling bath was then removed and the reaction stirred for 1 h while warming up to rt. A sol. of compound Y (2.00 g, 3.77 mmol) in THF (5 mL) was added dropwise, followed by Pd(PPh3)4 (126 mg, 0.109 mmol). The reaction mixture was stirred at rt for 2 h, then partitioned between EtOAc and aq. 1M NaOH, and the layers were separated. The aq. layer was extracted with EtOAc. The combined org. layers were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification by FC (heptane/EtOAc= 7/3) yielded the title compound (1.75 g, 73%). LC-MS: tR=1.20 min, ES+: 638.35.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[N:11]([C:16]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[F:28])=[O:20])=[CH:17][N:18]=3)[N:12]=[C:13](Cl)[CH:14]=2)[CH:5]=[CH:4][CH:3]=1.[C@H:29]1([NH2:36])[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1>CN1C(=O)CCC1>[NH2:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([NH:36][C:13]2[CH:14]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)[C:10]3[N:11]([C:16]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[F:28])=[O:20])=[CH:17][N:18]=3)[N:12]=2)[CH2:30][CH2:31]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Nc3cccc(Br)n3)cc(Cl)nn12
Solvent: CN1CCCC1=O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(Br)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 100 °C

Procedure:
A mixture of 8-(6-bromopyridin-2-ylamino)-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 17A (550 mg, 1.189 mmol) and trans-cyclohexane-1,4-diamine (1.086 g, 9.51 mmol) in NMP (4 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, and then added to ice water. The yellow solid was collected by filtration, and rinsed with water. The still wet solid pad was azeotroped with DCM/MeOH three times. The resulting solid residue was treated with a small amount of MeOH, filtered and dried to give 17B (456 mg, 71%) as a yellow solid. MS (m+1)=540. HPLC Peak Rt=2.870 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([NH:10]C(=O)C(C)(C)C)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([C:4]2[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Nc1cccc(C2CC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1cccc(C2CC2)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a solution of N-(6-cyclopropylpyridin-2-yl)pivalamide (4.25 gm, 19.49 mmol) in dioxane (34 ml) was added 9N HCl (34 ml). The mixture was stirred for 18 hours at 90° C. After cooling to 25° C., the pH of the reaction was adjusted with to achieve pH-9. The solution was diluted with ethyl acetate (200 ml) quantity and washed with saturated sodium bicarbonate. Next, the organic portion was dried over sodium sulfate and concentrated to get 2 gm (77.5% yield) clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12]Br)[C:5]([O:7][CH3:8])=[O:6].[C:14]([CH:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][NH:24][CH:21]1[CH2:22][CH2:23][CH:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:19][CH2:20]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(CBr)c(Br)c1
Reactant: CC(C)(C)C1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CNC2CCC(C(C)(C)C)CC2)c(Br)c1

Procedure:
To a solution of the product from Example 224 Step B (assume 4.76 mmol) in 5 mL of N,N-dimethylformamide was added 1.02 mL (5.71 mmol) of 4-tert-butylcyclohexylamine and 1.7 mL (9.76 mmol) of N,N-diisopropylethylamine. The resultant mixture was stirred at ambient temperature for 3 hours, diluted with ethyl acetate and the organic layer washed sequentially with three portions of water and one portion of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (biotage) using 5% ethyl acetate/hexanes as eluent to provide both the cis isomer and the desired trans isomer. 1H NMR (500 MHz, CD3OD) δ 8.18 (s, 1H), 7.97 (d, 1H, J=8 Hz), 7.58 (d, 1H, J=8 Hz), 3.93 (s, 2H), 3.91 (s, 3H), 2.43-2.37 (m, 1H), 2.08-2.01 (m, 2H), 1.85-1.79 (s, 2H), 1.19-4.99 (m, 5H), 0.86 (s, 9H). HPLC/MS (ESI) m/z (M+H)=384.2 (2.47 min.).
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:38][CH2:37][C:36]1=[O:40]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([NH:22][C:36](=[O:40])[CH2:37][CH3:38])[CH:23]=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 65 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and pyridine instead of N,N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (65% yield). HPLC: 92%, RT=4.234 min. MS: m/z=411 [M+H]+, RT=3.35 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]=[C:13]([F:18])[C:14](OC)=[O:15])[CH2:11][CH2:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]=[C:13]([F:18])[CH2:14][OH:15])[CH2:10][CH2:11]1
Reactant: COC(=O)C(F)=CC1(c2ccc(F)cc2F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(F)=CC1(c2ccc(F)cc2F)CC1
Yield: 69.8 %

Procedure:
The method of Example 9 was repeated using 1-(2,4-difluorophenyl)-1-(2-fluoro-2(methoxycarbonyl)ethenyl)cyclopropane (Example 7) (0.37 g), diethyl ether (10 ml) and lithium aluminium hydride (0.14 g) to yield the title compound (0.23 g, 71%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:13]([O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:13]([O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CCl
Reactant: Cc1nc2c(O)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OC(C)(C)C)c1COc1cccn2c(C)c(C)nc12

Procedure:
Starting from 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine (1.6 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (3.1 g), sodium iodide (1.8 g) and sodium carbonate (2.7 g) in acetone (350 ml) analogously using the process of Example B1 gives, after chromatography on silica gel (eluent toluene/dioxane 5:1) and recrystallization from cyclohexane, 3.0 g (78%) of the title compound of m.p. 128-131° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-])=O.C1(C2CCN(C(C3C=C(OC)C(OC)=C(OC)C=3)=O)CC2)C=CC=CC=1>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: COc1cc(C(=O)N2CCC(c3ccccc3)CC2)cc(OC)c1OC
Solvent: CCO
Product: Nc1ccc2[nH]ccc2c1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of 5-nitro-1H-indole (11 g, 67.9 mmol) and Pd/C (5%; 1g), dissolved in ethanol (50 mL), was hydrogenated for 3 h at 40 psi. The reaction mixture was filtered and the excess of ethanol was evaporated under reduced pressure. Solid product was recrystallized from hexane to obtain the pure compound 5-aminoindole (55-1). Yield: 92.5%. 1H NMR (500 MHz, CDCl3): δ 7.96 (br, 1H), 7.20 (d, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 6.67 (dd, 1H), 6.37 (s, 1H), 3.50 (s, 2H). MS (ESI) m/z 133.0 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])(=O)C.CCO.[OH-].[Na+].O>CCOCC>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([CH:11]=1)[CH2:5][OH:4]
Reactant: CC(=O)OCc1cc(Br)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: OCc1cc(Br)ccc1F

Procedure:
A solution of the compound (1b) (3.2 g, 14.5 mmol), EtOH (20 mL) and 1 N NaOH (20 mL, 20 mmol) was stirred at reflux under N2 for 1.5 hours. The reaction mixture was cooled and distributed between H2O (150 mL) and Et2O (150 mL). The organic layer was separated and washed with H2O (2×100 mL), dried and the clear faint yellow solution was evaporated. Distillation of the residue provided the compound (1c) as a clear colorless oil; bp 82°-87° C. (0.4 mm); NMR 3.3 (H, br s), 4.6 (2 H, s), 6.81 (H3, t, J=9 Hz), 7.15-7.37 (H4, m), 7.44 (H6, dd, J=3 and 6 Hz).
Reaction SMILES: C(O)C.[NH2:4][C:5]1([CH3:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:4][C:5]1([CH3:11])[CH2:10][CH2:9][N:8]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:7][CH2:6]1
Reactant: Clc1ncccn1
Reactant: CC1(N)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1(N)CCN(c2ncccn2)CC1
Yield: 65.1 %

Procedure:
2 ml of an ethanol suspension containing 260 mg of 4-amino-4-methylpiperidine (synthesized according to a method described in U.S. Pat. No. 5,821,240), 237 mg of 2-chloropyrimidine and 858 mg of potassium carbonate was stirred at 50° C. for 12 hours. The reaction mixture was poured into water, and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography [solvent: chloroform-methanol-aqueous ammonia (300:10:1)] to obtain 259 mg of 4-amino-4-methyl-N-(2-pyrimidinyl)piperidine (Reference Example 8-1 in Table 9).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]1([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]3([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: N#CC1(S(=O)(=O)c2ccccc2Br)CCCC1
Product: N#CC1(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)CCCC1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-((2-bromophenyl)sulfonyl)cyclopentanecarbonitrile. MS (ESI): mass calcd. for C22H19FN4O2S, 422.12; m/z found, 423.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 2H), 8.21 (d, J=8.0, 1H), 7.91 (m, 1H), 7.86-7.79 (m, 1H), 7.57 (m, 1H), 7.52 (d, J=7.6, 1H), 7.37 (dd, J=11.8, 1.4, 1H), 7.29 (dd, J=8.0, 1.6, 1H), 6.92 (s, 2H), 2.22-2.07 (m, 4H), 1.72-1.68 (m, 4H).
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH2:33][CH2:34][CH2:35][NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)(=O)=O)=CC=1.C(Cl)Cl.CCOC(C)=O>CN(C=O)C>[C:43]([C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH2:35][CH2:34][CH2:33][N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:38][CH:39]=1)#[N:44]
Reactant: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Temperature: 90 °C
Reaction time: 5 h
Yield: 76.9 %

Procedure:
To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.5 g, 16.5 mmol; from Preparation B above) in DMF (75 mL) was added K2CO3 and 3-(4-cyanoanilino)propyl 4-methylbenzenesulfonate (5.5 g, 16.5 mmol; from Preparation D, step (b) above). The resulting solution was warmed to 90° C., stirred for 5 h, cooled and concentrated in vacuo. The residue was suspended in H2O and extracted with CH2Cl2 (3×). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash chromatography on silica gel eluting with CH2Cl2:EtOAc (3:1) gave 4.7 g (77%) of the title compound as a solid.