Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:14]1[S:18][CH:17]=[C:16]([C:19]#[N:20])[CH:15]=1)([CH:11]([CH3:13])[CH3:12])[CH2:4][CH2:5][C:6](OCC)=[O:7])#[N:2].[BH4-].[Li+].Cl.O>C1COCC1>[C:1]([C:3]([C:14]1[S:18][CH:17]=[C:16]([C:19]#[N:20])[CH:15]=1)([CH:11]([CH3:13])[CH3:12])[CH2:4][CH2:5][CH2:6][OH:7])#[N:2]
Reactant: CCOC(=O)CCC(C#N)(c1cc(C#N)cs1)C(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(C#N)(CCCO)c1cc(C#N)cs1

Procedure:
Ethyl 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexanate (0.55 g) was dissolved in THF (10 ml), lithium borohydride (46 mg) was added, and the mixture was heated under reflux for 1.5 hours. After cooling as it was to room temperature, 1N aqueous hydrochloric acid and water were added at 0° C., and the mixture was extracted with ethyl acetate. The mixture was further washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give the title compound pale as a yellow oil (1.25 g, 47%). Further, the catalyst was filtered off, and the filtrate was evaporated. The resulting residue was purified by preparative thin layer silica gel column chromatography (hexane/ethyl acetate system), to give the title compound as a pale yellow oil (0.39 g, 83%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:12])[C:8](=[S:11])[NH:9][N:10]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.ClCCl.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH:15]1([CH2:14][S:11][C:8]2[N:7]([CH3:12])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[N:10][N:9]=2)[CH2:17][CH2:16]1
Reactant: Cn1c(CCCCO)n[nH]c1=S
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(CCCCO)nnc1SCC1CC1
Temperature: 60 °C

Procedure:
5-(4-hydroxybutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.3 g), (bromomethyl)cyclopropane (0.17 ml) and triethyl ammine (0.27 ml) were dissolved in dimethylformamide (2 ml). Reaction was heated at 60° C. for 2 h. Dichloromethane and NaHCO3 saturated solution were added. Solvent was removed, under reduced pressure to give a crude that was purified by Silica column (eluting with DCM/MeOH from 0 to 10%) to give the title compound (0.2 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-trifluoromethyl-phenylboronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(4-trifluoromethyl-phenyl)-6-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 399(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:29](O)/[CH:30]=[CH:31]\[CH2:32][OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:29][CH:30]=[CH:31][CH2:32][OH:33])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: OC/C=C\CO
Product: O=C1c2ccccc2C(OCC=CCO)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 57.9 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis-butenediol (445 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow oil (272 mg, 58%). 1H NMR (300 MHz, CDCl3): 8.04-8.00 (m, 2H, O2N—C—CH), 7.93-7.91 (m, 1H, C(O)═C═CH), 7.57-7.51 (m, 2H, Ar—H), 7.39-7.36 (m, 2H, Ar—H), 7.23-7.12 (m, 5 H, Ar—H), 5.62-5.53 (m, 1H, OCH2CH), 5.35-5.26 (m, 1H, OCH2CH), 4.64 and 4.26 (dd: AB, J=15.0 Hz, 2H, N—CH2), 3.79 (d, J=6.6 Hz, HO—CH2), 3.48-3.29 (m, 2H, O—CH2). 13C NMR (75 MHz, CDCl3): 168.17, 147.45, 145.07, 144.60, 136.86, 134.98, 133.07, 132.00, 131.44, 130.24, 130.02, 128.71, 127.99, 126.79, 123.89, 123.35, 95.00, 59.20, 58.48, 42.57. m/z (ES): 465 [M+H]+. Anal.: calc. for C25H21ClN2O5: C, 64.59; H, 4.55; N, 6.02. Found: C, 64.39; H, 4.67; N, 5.67.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@@:4]([CH2:1][CH3:3])([OH:12])[CH2:8][CH2:7][N:6]1[C:20]1[CH:21]=[C:14]([F:13])[C:15]([C:16]#[N:17])=[C:18]([F:23])[CH:19]=1)[CH3:11]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2cc(F)c(C#N)c(F)c2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (197 mg), 2,4,6-trifluorobenzonitrile (295 mg) and lithium carbonate (192 mg), the title compound was obtained as a colorless solid (yield: 157 mg, yield: 54%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([N+:23]([O-])=O)[CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2>CCO.[Pd]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=3)=[CH:12][CH:11]=1)[CH2:2]2
Reactant: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1N
Yield: 98 %

Procedure:
The product of Example 28D (200 mg, 0.59 mmol) was hydrogenated under the catalysis of Pd/C (Aldrich, 10 wt. %, 50 mg) in EtOH (10 mL) under hydrogen at ambient temperature for 10 h. After the reaction went to completion, the catalyst was removed through a short column of diatomaceous earth (˜2 g) and the filtrate was washed with EtOH (2×5 mL). The ethanol solution was concentrated to give the title compound (180 mg, yield, 98%). 1H NMR (500 MHz, CD3-OD) δ 1.58-1.73 (m, 1H), 1.76-2.00 (m, 2H), 2.06-2.27 (m, 1H), 2.29-2.47 (m, 1H), 2.81-3.20 (m, 5H), 3.52-3.68 (m, 1H), 5.11-5.57 (m, 1H), 6.78 (d, J=8.2 Hz, 1H), 7.12-7.26 (m, 2H), 7.32 (d, J=2.1 Hz, 1H), 7.92 (d, J=9.2 Hz, 1H) ppm. MS (DCI/NH3): 312 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].[NH2:32][C:33]1([C:43]([OH:45])=[O:44])[CH:40]2[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:42][CH:34]1[CH2:35]3)[CH2:39]2>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:32][C:33]3([C:43]([OH:45])=[O:44])[CH:40]4[CH2:39][CH:38]5[CH2:37][CH:36]([CH2:35][CH:34]3[CH2:42]5)[CH2:41]4)=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31]
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Product: Cc1ccccc1-c1ccc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Product: Cl
Yield: 121.1 %

Procedure:
According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 4.65 g (10.6 mmol) of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylate and 2.38 g (12.18 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain 4.1 g of 2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride in the form of white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=O)=[N:6][C:7]=1[CH3:8].[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc(C(=O)O)nc1C
Product: Cc1ccc(C(=O)Nc2nnn[nH]2)nc1C
Yield: 55.4 %

Procedure:
0.55 g of 5,6-dimethyl-2-pyridinecarboxylic acid, 0.77 g of N,N'-carbonyldiimidazole and 0.48 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.44 g of N-(5-tetrazolyl)-5,6-dimethyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][C:7]1=[O:20])[CH3:4].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=1>>[CH2:29]([O:28][C:24]1[CH:23]=[C:22]([C:7]2([OH:20])[CH2:8][CH2:9][CH:10]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][CH:6]2[CH2:5][N:3]([CH3:4])[CH3:2])[CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: CN(C)CC1CC(CCc2ccccc2)CCC1=O
Agent: Cl
Product: CN(C)CC1CC(CCc2ccccc2)CCC1(O)c1cccc(OCc2ccccc2)c1
Yield: 87 %

Procedure:
The base of compound (48) was reacted with 1-bromo-3-benzyloxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 6:1 ether/methanol via a silica gel column. Compound (50) was obtained in a yield of 87% theoretical.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[C:30](=[O:32])=[O:31].Cl>O1CCCC1.O>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2ncc(-c3ccc(Br)cc3)s2)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCOc1ccc(-c2ncc(-c3ccc(C(=O)O)cc3)s2)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution of 2-(4-pentyloxyphenyl)-5-(4-bromophenyl)thiazole (2.3 g) in dry tetrahydrofuran (60 ml) was cooled to −60° C., and a solution of n-butyllithium (1.66M in n-hexane, 4.46 ml) was added slowly to maintain the reaction temperature at −60° C. After stirring for 1 hour, a solution of n-butyllithium (1.66M in n-hexane, 1.0 ml) was additionally added. The reaction mixture was allowed to warm to −40° C. After stirring for 30 minutes, dry-ice (5 g) was added. The reaction mixture was allowed to warm to room temperature over 30 minutes. To the reaction mixture was added water (25 ml) and 0.5N-hydrochloric acid (100 ml), then extracted with dichloromethane (500 ml). The organic layer was washed with brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in acetonitrile, and collected by filtration to give 4-[2-(4-pentyloxyphenyl)thiazol-5-yl]benzoic acid (1.70 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:16])C(=O)C1>CN(C=O)C>[Cl:16][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(N)n1
Solvent: CN(C)C=O
Product: Cc1nc(N)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6-methylpyridin-2-amine (10.80 g, 100 mmol) in 50 mL of dry DMF was added a solution of NCS (13.4 g, 100 mmol) in 60 mL of dry DMF dropwise at 0° C. over 20 min. The resulting brown yellow solution was stirred at 0° C. for 1 hour, and at room temperature for 3 hours, then poured to 300 mL of ice-water. The resulting mixture was extracted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via column chromatograph to afford 5-chloro-6-methylpyridin-2-amine.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.COC1C=CC(C[O:22][CH:23]([C:29]2[CH:34]=[CH:33][C:32]([N:35]([CH2:39][C:40]#[C:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:36](=[O:38])[CH3:37])=[CH:31][CH:30]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=CC=1>C(Cl)(Cl)Cl.O>[OH:22][CH:23]([C:29]1[CH:30]=[CH:31][C:32]([N:35]([CH2:39][C:40]#[C:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:36](=[O:38])[CH3:37])=[CH:33][CH:34]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc(N(CC#CCCCC(=O)OC)C(C)=O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCC(O)c1ccc(N(CC#CCCCC(=O)OC)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
4,5-Dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile (19 mg, 0.081 mmol) was added to a solution of the MPM-ether 104 (35 mg, 0.071 mmol) in CHCl3 (1.6 mL) and H2O (0.1 mL) at 0° C. After stirring for 2 h at 0° C. the reaction was quenched with sodium bicarbonate and extracted with EtOAc. The organic portion was washed with saturated aqueous sodium hydrogen sulfate and brine, then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 3:2 hex/EtOAc) to yield 23 mg (87%) of the hydroxyl-ester 105.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.N[C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1.CC(C)[N:43]=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([NH:43][C:39]3[CH:40]=[CH:31][CH:32]=[CH:33][C:34]=3[C:35]([O:37][CH3:38])=[O:36])=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)N=C=NC(C)C
Reactant: COc1cn(C(CC2CCCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)C(CC1CCCCO1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
2.20 g (5.28 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoic acid (mixture of racemic diastereomers), 798 mg (5.28 mmol) of methyl 4-aminobenzoate, 750 mg (5.28 mmol) of Oxima and 822 μl (5.28 mmol) of DIC in 110 ml of dimethylformamide were reacted according to General Method 5B. The reaction mixture was purified by flash chromatography (80 g cartridge, 60 ml/min, cyclohexane/ethyl acetate gradient). Yield: 905 mg (31% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][C:22]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=4[C:15]=3[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][C:22]4[CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[C:15]=3[CH:16]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc(F)cc4)cc3c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1)c1ccc2oc3c(c2c1)CNCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To the product obtained in step A (150 mg, 0.31 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.6 mL). After stirring for 2 h at ambient temperature the reaction mixture was quenched with 10% sodium bicarbonate solution (20 mL) and extracted with dichloromethane. The organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 90:10 dichloromethane/methanol) to give 8-(4-fluorophenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (60 mg, 52%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.03 (d, J=1.8 Hz, 1H), 8.00-7.92 (m, 2H), 7.78 (dd, J=8.7, 2.1 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.21-7.10 (m, 2H), 4.00 (t, J=2.1 Hz, 2H), 3.25 (t, J=5.7 Hz, 2H), 2.84-2.76 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C#Cc2cccc(N)c2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccnc(CCc2cccc(N)c2)c1
Yield: 47.3 %

Procedure:
To a mixture of tert-butyl {2-[(3-aminophenyl)ethynyl]pyridin-4-yl}carbamate (250 mg, 1.62 mmol) (prepared in Example C12, step A) in methanol (10 mL) was added 10% palladium on carbon (0.30 g, 0.24 mmol). The reaction mixture was hydrogenated at 50 psi overnight. The resultant mixture was filtered and concentrated to provide the desired product (240 mg, 95%) as a white solid. LCMS for C18H24N3O2 (M+H)+: m/z=314.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:15][CH:16]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C(Cl)[Cl:29].CO.[ClH:33]>O1CCOCC1>[ClH:29].[ClH:33].[Br:1][C:2]1[CH:3]=[C:4]([O:15][CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OC2CCN(C(=O)OC(C)(C)C)C2)n1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1csc(Nc2ncc(Br)cc2OC2CCNC2)n1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A mixture of tert-butyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidine-1-carboxylate (prepared according to Example 61; 550 mg, 1.21 mmol) and CH2Cl2 (10 mL) and MeOH (2 mL) was stirred at room temperature. 4N HCl in dioxane (5 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was concentrated and dissolved in small amount of CH2Cl2/methanol and added to vigorously stirred ether and filtered to afford N-(5-bromo-3-(pyrrolidin-3-yloxy)pyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride (478 mg, 92.4% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.18 (bs, 1H), 9.80 (bs, 1H), 9.27 (bs, 1H), 8.09 (d, 1H), 7.83 (d, 1H), 6.80 (s, 1H), 5.42 (m, 1H), 3.62-3.30 (m, 4H), 2.31 (s, 3H), 2.22 (m, 2H); Mass spectrum (apci) m/z 357.0 (M+H-2HCl).
Reaction SMILES: [OH-:1].[K+].C(OC1C=CC(N[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:31]4[C:26](=[CH:27][C:28](Cl)=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=CC=1)(C)C.[CH3:33][OH:34]>>[C:19]([O:1][C:14]([N:16]1[CH2:17][CH2:18][CH:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:33])=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:22])([CH3:20])[CH3:18]
Reactant: [OH-]
Reactant: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(Cl)ccc34)CC2)cc1
Reactant: CO
Agent: [K+]
Product: COc1ccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Solid KOH (224 mg, 4 mmol) was added to a solution of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (29a; 41 mg, 0.1 mmol), prepared as described in Example 29, in anhydrous MeOH (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (31a). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-methoxy-quinazolin-4-yl)-piperidine (31b) as a di-HCl salt. To a suspension of (31b) in anhydrous MeOH (2 mL), was added DIEA (45 μL, 0.25 mmol) followed by (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (48 mg, 0.15 mmol), as prepared in Example 1a, and the mixture was stirred at rt for 1 h. It was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 1% MeOH/DCM) to obtain 5.4 mg (13% overall yield from 29a) of pure 4-(7-methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): δ 9.14 (s, 1H), 8.06 (d, 1H), 7.35 (d, 1H), 7.30-7.25 (m, 3H), 6.84 (d, 2H), 6.30 (s, 1H), 4.48 (m, 1H), 4.26 (m, 2H), 3.99 (s, 3H), 3.69 (m, 1H), 3.14 (m, 2H), 2.23-2.05 (m, 2H), 2.03-1.92 (m, 2H), 1.31 (d, 6H). LC/MS (ESI): calcd mass 420.2, found 421.4 (MH)+.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.P(Br)(Br)[Br:14].CCO[C:20](C)=[O:21]>CN(C=O)C>[Br:14][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:21][CH3:20])[CH:2]=[CH:11]2
Reactant: BrP(Br)Br
Reactant: CCOC(C)=O
Reactant: Oc1ccnc2cc(F)cnc12
Solvent: CN(C)C=O
Product: COc1ccc2nccc(Br)c2n1
Temperature: 25 °C

Procedure:
To a suspension of 7-fluoro-1,5-naphthyridin-4-ol (400 mg, 2.43 mmol) in DMF (8 mL), was added PBr3 (659.65 mg, 2.43 mmol) dropwise at 50° C. for 10 minutes. After complete addition of PBr3, the suspension became homogeneous and a brown precipitate was obtained over a period of 30 minutes. The reaction was monitored by TLC (TLC eluent: 50% EtOAc in petroleum ether). After completion of reaction, the mixture was cooled to ambient temperature to generate more precipitate. The precipitate was filtered and washed with Et2O (15 mL) and dried under vacuum to afford a brown colored hydro bromide salt of 8-bromo-2-methoxy-[1,5]naphthyridine which was free-based using saturated bicarbonate solution (10 mL) and product was extracted into EtOAc (2×25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 8-bromo-3-fluoro-1,5-naphthyridine as a brown solid, (200 mg, 36%). 1H NMR (300 MHz, DMSO-d6): δ 9.19 (d, J=2.4 Hz, 1H), 8.84 (d, J=4.8 Hz, 1H), 8.44 (dd, J=2.8 & 9.2 Hz, 1H), 8.23 (d, J=4.8 Hz, 1H). m/z (ESI) 227.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][C:10]([CH3:15])([CH3:14])[C:11](Br)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[Br:9][C:10]([CH3:15])([CH3:14])[C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:12]
Reactant: Nc1ccccc1O
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Br)C(=O)Nc1ccccc1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 921 %

Procedure:
To a stirred solution of 2-aminophenol (10 g, 9.2 mmol) in DCM (92 mL) at 0° C. was added 2-bromoisobutyryl bromide (11.4 mL, 9.17 mmol) followed by triethyl amine (12.7 mL, 9.2 mmol) and stirred the reaction mixture at 0° C. for 4 h. Reaction mixture was diluted with DCM 100 mL and then washed with water 100 mL dried over sodium sulfate, concentrated on rotavap to give 2-Bromo-N-(2-hydroxy-phenyl)-2-methyl-propionamide (21.8 g) brown solid which was used for next reaction without purification