Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH2:18])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN(C=O)C>[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH2:18])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)[CH:3]=2)[CH2:30][CH2:29]1
Reactant: Nc1nc2c(Oc3cc(Cl)ncn3)cccc2s1
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2c(Oc3cc(N4CCC(C(F)(F)F)CC4)ncn3)cccc2s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine, (Example 133(a)), (300 mg, 1.1 mmol) in dry DMF (3.0 mL) stirred at room temperature was added K2CO3 (590 mg, 4.3 mmol) and 4-(trifluoromethyl)piperidine hydrochloride (410 mg, 2.1 mmol, Matrix Scientific). The reaction mixture was stirred at 80° C. for 4 h. The resulting mixture was allowed to cool to room temperature and treated with water (20 mL). The resulting precipitate was collected by filtration, washed with water (2×), MeOH (1×), and EtOAc (3×), then dried in vacuum. The title compound was obtained as a white amorphous solid. MS (ESI, pos. ion) m/z: 396 (M+1). Anal. Calcd for C17H16F3N5OS: C, 51.64; H, 4.08; N, 17.71; F, 14.41. Found: C, 51.62; H, 4.09; N, 17.61; F, 14.33.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[O:17])=[CH:11][CH:10]=1)=O)(C)(C)C.O1CCOCC1.Cl>O1CCOCC1>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.7 %

Procedure:
To a solution of the Product from Example 3A (0.245 g, 0.56 mmol) in dioxane (5 mL) was added 4M HCl dioxane (2.8 mL, 11.2 mol) and the mixture was stirred at ambient temperature for 17 hours. The mixture was concentrated and azeotroped with toluene to give a tan solid (0.18 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]S(N)(=O)=O)[CH:12]=[CH:13][CH:14]=2)[N:3]=1.ClC1N=C(Cl)N=CN=1.NC1C=C(C[CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])C=CC=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: Nc1cccc(CCS(N)(=O)=O)c1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: Clc1ncnc(Cl)n1
Product: NS(=O)(=O)CCc1cccc(Nc2ncnc(Cl)n2)c1

Procedure:
A4 was prepared following the general procedure reported for A1 using 2,4-dichloro-1,3,5-triazine and 2-(3-aminophenyl)ethanesulfonamide A3 as reacting agents. The crude product was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 4:1) to yield the desired product A5 (54%, 65% purity) as a brown solid. MS (ES) C11H12ClN5O2S requires: 313. found: 314 (M+H)+.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:19](=[O:21])[CH3:20])[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CNCCS2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCSc2ccccc2C1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (5 g, 30.3 mmol) in dry dichloromethane (100 mL) was added triethylamine (5.06 mL, 36.3 mmol) at room temperature, followed by the addition of acetic anhydride (3.43 mL, 36.3 mmol) dropwise at 0° C. under nitrogen. The resulting solution was stirred for 1 hour whilst allowing the temperature to rise slowly to room temperature. The mixture was washed with brine (50 mL×2), dried over sodium sulfate, filtered and concentrated in vacuo to afford 6.28 g of product as yellow oil, which was used for next step without further purification.
Reaction SMILES: C1C=CC(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)=CC=1.[CH2:18]=[C:19]([C:21]1[CH:22]=[C:23]([C@@H:27](O)[CH3:28])[CH:24]=[N:25][CH:26]=1)[CH3:20].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:15]([C@@H:27]([C:23]1[CH:24]=[N:25][CH:26]=[C:21]([C:19]([CH3:20])=[CH2:18])[CH:22]=1)[CH3:28])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C=C(C)c1cncc([C@H](C)O)c1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C=C(C)c1cncc([C@@H](C)N=[N+]=[N-])c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
DPPA (0.55 mL, 2.55 mmol) was added to (S)-1-(5-(prop-1-en-2-yl)pyridin-3-yl)ethanol (347 mg, 2.13 mmol) in toluene (5 mL) and the reaction is cooled to 0° C. DBU (0.38 mL, 2.55 mmol) was added, the reaction was allowed to warm to room temperature and stirred overnight, diluted with EtOAc and washed with water. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (35% EtOAc in hexanes) to provide 340 mg of (R)-3-(1-azidoethyl)-5-(prop-1-en-2-yl)pyridine.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[CH3:1][N:2]1[C:7](/[CH:8]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: O=Cc1ccccc1
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Solvent: C1CCNCC1
Solvent: CCO
Product: Cn1c(/C=C/c2ccccc2)c([N+](=O)[O-])c(=O)n(C)c1=O
Yield: 60.3 %

Procedure:
A mixture of 1,3,6-trimethyl-5-nitro-1H-pyrimidine-2,4dione (3.00 g, 15.06 mmol), benzaldehyde (1.58 ml, 15.56 mmol), piperidine (1.41 ml, 15.56 mmol) and a 3 Å molecular sieve (6.00 g) in ethanol (70 ml) was refluxed for 4 hours, filtered and the solid was treated with a mixture of chloroform and methanol. The resulting suspension was filtered again and the filtrates were evaporated. The residue was triturated with diethyl ether and the precipitate collected by filtration and dried under vacuum to yield 1,3-dimethyl-5-nitro-6-((E)styryl)-1H-pyrimidine-2,4-dione (2.61 g, 60%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(#N)C>[CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]([C:17](=[O:19])[CH3:18])[C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Solvent: CC#N
Product: CC(=O)N1CCCC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 61 %

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.874 g, 0.00397 mol), acetic anhydride (8.418 mL) and acetonitrile (10 mL) were combined in a round bottom flask. The mixture was stirred at room temp for 17 hours and then heated at 60° C. for 2 days. The mixture was concentrated under reduced pressure, then purified by normal phase chromatography eluting with 10% to 50% ethyl acetate in hexane to yield a yellow oil, 1-(5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (1.04 g, 61%). LCMS: m/z=263.25 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.15 (m, 1H), 7.98 (m, 1H), 7.65 (d, 1H, J=8.6 Hz), 4.82 (m, 1H), 2.60 (m, 1H), 2.24 (m, 1H), 1.95 (s, 3H), 1.81 (m, 1H), 1.70 (m, 1H), 1.56 (m, 6H), 1.28 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:68])([CH3:67])[O:3][C:4](=[O:66])[NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12](=[O:65])[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:20](=[O:64])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28](=[O:63])[NH:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][C:36](=[O:62])[NH:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][C:44](=[O:61])[NH:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][C:52](=[O:60])[NH:53][CH2:54][C:55]([O:57]CC)=[O:56].[OH-].[Li+]>C1COCC1>[CH3:1][C:2]([CH3:68])([CH3:67])[O:3][C:4](=[O:66])[NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12](=[O:65])[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:20](=[O:64])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28](=[O:63])[NH:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][C:36](=[O:62])[NH:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][C:44](=[O:61])[NH:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][C:52](=[O:60])[NH:53][CH2:54][C:55]([OH:57])=[O:56]
Reactant: CCOC(=O)CNC(=O)OCCOCCNC(=O)OCCOCCNC(=O)OCCOCCNC(=O)OCCOCCNC(=O)OCCOCCNC(=O)OCCOCCNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOCCOC(=O)NCCOCCOC(=O)NCCOCCOC(=O)NCCOCCOC(=O)NCCOCCOC(=O)NCCOCCOC(=O)NCC(=O)O
Yield: 95.6 %

Procedure:
Ethyl 54,54-dimethyl-4,12,20,28,36,44,52-heptaoxo-5,8,13,16,21,24,29,32,37,40,45,48,53-tridecaoxa-3,11,19,27,35,43,51-heptaazapentapentacontan-1-oate (Compound 13, 2.4 g, 0.0025 mol) was dissolved in THF (30 mL) and then stirred. After slowly adding 2 N lithium hydroxide aqueous solution (8 mL), the mixture was stirred at room temperature for 40 minutes. After removing THF from the reaction mixture, 1 N HCl aqueous solution was slowly added for acidification. After extracting 3 times with dichloromethane, the organic layer was separated, dried with magnesium sulfate, and then concentrated. The target compound 54,54-dimethyl-4,12,20,28,36,44,52-heptaoxo-5,8,13,16,21,24,29,32,37,40,45,48,53-tridecaoxa-3,11,19,27,35,43,51-heptaaza-1-pentapentacontanoic acid (Compound 14, 2.3 g, 99.1%) was yielded.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][CH3:15].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1>>[C:33]([O:32][C:31](=[O:37])[NH:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=4)[N:5]=[CH:4][C:3]=3[C:13](=[O:16])[CH2:14][CH3:15])=[CH:23][N:22]=2)[CH2:25]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 109.8 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)propan-1-one (250 mg, 0.98 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (430 mg, 1.5 mmol) to afford the desired product (550 mg, crude) as an dark brown solid: 1H NMR (500 MHz, CDCl3) δ 11.29 (s, 1H), 9.03 (s, 1H), 8.11 (d, J=9.0 Hz, 1H), 8.01 (d, J=3.0 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.31-7.29 (m, 1H), 6.72 (d, J=9.0 Hz, 1H), 4.79 (br s, 1H), 3.90-3.61 (m, 4H), 3.51-3.25 (m, 2H), 3.07 (q, J=7.0 Hz, 2H), 1.96-1.84 (m, 1H), 1.82-1.70 (m, 1H), 1.72-1.55 (m, 1H), 1.45 (s, 9H), 1.26 (t, J=7.0 Hz, 3H); ESI MS m/z 511 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.[B:22](OC)([O:25]C)[O:23]C>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([CH:10]=[C:9]([B:22]([OH:25])[OH:23])[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1ccc2ccc(Cl)nc21
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: Cn1c(B(O)O)cc2ccc(Cl)nc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 163.1 %

Procedure:
To a solution of 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine (1.02 g, 6.12 mmol)) in THF (60 mL) at −78° C. was added 1.7 M t-BuLi in pentane (9.00 mL, 15.31 mmol) and the mixture was stirred at −78° C. for 2 h. Trimethyl borate (1.026 mL, 9.18 mmol) was added at −78° C. and the mixture was allowed to warm to room temperature, and stirred at room temperature overnight. Water (2 mL) was added and the mixture was concentrated in vacuo. The solid was subjected to high vacuum overnight to afford 2.1 g of 6-chloro-N-methyl-7-aza indole-2-boronic acid. ESI-MS: m/z 211.1 (M+H)+
Reaction SMILES: O=C1NC2[C:14]3[CH:6]([CH2:7][N:8]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].IC.[CH3:28][N:29]([CH:31]=[O:32])[CH3:30]>>[C:6]([CH:16]([N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:28]3[N:29]([CH3:30])[C:31](=[O:32])[CH2:3][CH2:4][CH2:5][CH:6]([C:14]=23)[CH2:7]1)[C:17]([OH:19])=[O:18])([CH3:14])([CH3:7])[CH3:5]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)CN1CC2CCCC(=O)Nc3cccc1c32
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN1C(=O)CCCC2CN(C(C(=O)O)C(C)(C)C)c3cccc1c32
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl (6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)acetate, enantiomer A, from Step F (20 mg, 0.063 mmol) in DMF (0.5 mL) at ambient temperature was added sodium hydride (3 mg of a 60% dispersion in mineral oil, 0.075 mmol). The reaction mixture was stirred for 5 min, then iodomethane (10 mg, 0.070 mmol) was added and stirring was continued for 10 min. The reaction was quenched with saturated aqueous NaHCO3 (1 mL) and extracted with EtOAc (2×3 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=331 (M+1).
Reaction SMILES: C1(C2C=CC(C(Cl)=O)=CC=2)C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][CH:22]=[C:21]2[O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[C:33]([F:38])[CH:32]=1.[C:39]1([C:45]2[CH:50]=[CH:49][C:48]([C:51]([N:53]=[C:54]=[S:55])=[O:52])=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[C:39]1([C:45]2[CH:50]=[CH:49][C:48]([C:51]([N:53]=[C:54]=[S:55])=[O:52])=[CH:47][CH:46]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1.[C:39]1([C:45]2[CH:50]=[CH:49][C:48]([C:51]([NH:53][C:54]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([O:30][C:21]4[C:20]5[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][CH3:16])[CH:19]=5)[N:24]=[CH:23][CH:22]=4)=[CH:32][C:33]=3[F:38])=[S:55])=[O:52])=[CH:47][CH:46]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C(N=C=S)c1ccc(-c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(-c5ccccc5)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
4-Phenyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-phenyl-1benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-phenyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 47%).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][OH:9])[N:7]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[N:23]([CH3:29])[C:22]=3[CH:30]=2)[C:14](=[O:31])[CH:13]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH:26]1([C:24]2[N:23]([CH3:29])[C:22]3[CH:30]=[C:18]([N:15]4[CH:16]=[CH:17][C:12]([O:9][CH2:8][C:6]5[N:7]=[C:3]([CH:2]([F:10])[F:1])[S:4][CH:5]=5)=[CH:13][C:14]4=[O:31])[CH:19]=[CH:20][C:21]=3[N:25]=2)[CH2:27][CH2:28]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Reactant: OCc1csc(C(F)F)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)F)n4)cc3=O)cc21
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To a suspension of (2-(difluoromethyl)thiazol-4-yl)methanol (44 mg) and 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)-one (66.5 mg) in toluene (1 ml) was added potassium tert-butoxide (49.8 mg) at 100° C., and the mixture was stirred at 100° C. under dry atmosphere (CaCl2 tube) for 30 min. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by recrystallization from EtOH-water to give the title compound (47.7 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Br-:32].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[C:11]([Br:32])=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: O=C1c2c(OCc3ccccc3)c(=O)ccn2CCN1Cc1ccc(Cl)c(Cl)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1c2c(OCc3ccccc3)c(=O)c(Br)cn2CCN1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 62.3 %

Procedure:
To a solution of 9-benzyloxy-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (3.8 g) obtained in Example 1, Step 3 in chloroform (90 ml)-methanol (60 ml) was added phenyltrimethylammonium tribromide (5.0 g) and the mixture was stirred at room temperature for 13 hr. An aqueous sodium sulfite solution was added to the reaction mixture and the mixture was extracted twice with chloroform. The combined extract was washed with brine and purified as it was by silica gel column chromatography (chloroform-methanol=19:1–10:1) to give 9-benzyloxy-7-bromo-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (2.44 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1C[N:35]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.C(N)C>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:35][CH2:34][CH3:33])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added ethanamine hydrochloride (7.4 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of ethanamine hydrochloride were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-ethylacetamide. (19 mg, 0.043 mmol, 31%)
Reaction SMILES: [C:1]([C:4]1[N:8]([CH:9]([CH3:11])[CH3:10])[C:7]([CH3:12])=[N:6][C:5]=1[CH3:13])(=[O:3])[CH3:2].C[C:15]([N:17]([CH3:19])[CH3:18])=O>CN(C=O)C>[CH3:15][N:17]([CH3:19])[CH:18]=[CH:2][C:1]([C:4]1[N:8]([CH:9]([CH3:11])[CH3:10])[C:7]([CH3:12])=[N:6][C:5]=1[CH3:13])=[O:3]
Reactant: CC(=O)c1c(C)nc(C)n1C(C)C
Reactant: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C)n(C(C)C)c1C(=O)C=CN(C)C
Yield: 13 %

Procedure:
5-Acetyl-1-isopropyl-2,4-dimethylimidazole (Method 8; 3g, 16.5 mmol) was dissolved in a mixture DMF.DMA (100 ml) and the mixture heated under reflux, under an atmosphere of nitrogen, for 18 hours. The volatiles were evaporated in vacuo. The residue was purified by flash silica chromatography DCM:MeOH (increasing in polarity from 100:0 to 95:5) to give the title compound (510 mg, 13%) as an orange oil. NMR 1.38 (d, 6H), 2.18 (s, 3H), 2.30 (s, 3H), 2.83 (s, 3H), 3.08 (s, 3H), 4.72 (q, 1H), 5.21 (d, 1H), 7.46 (d, 1H); m/z 236
Reaction SMILES: [Li]CCCC.[S].Cl.S1C(SC[C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=O)=CC2C=CC=CC1=2.S1C(S)=CC2C=CC=CC1=2.[H-].[Na+].ClCC(N1C2C(=CC=CC=2)CCC1)=[O:46]>CCOCC.C1COCC1>[NH:17]1[CH2:15][CH2:18][CH2:19][C:20](=[O:46])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]1=2
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: O=C(CSc1cc2ccccc2s1)N1CCCc2ccccc21
Agent: Cl
Agent: Sc1cc2ccccc2s1
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCCNc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Compound 71 (1.75 g, 13.0 mmol) was dissolved in 40 mL of dry Et2O under N2 and the solution was cooled to 40° C. nBuLi (2.5 M solution in hexane, 5.7 mL, 14.3 mmol) was added and the reaction mixture was allowed to warm up to 0° C. during 1 h and then sulfur (0.414 g, 13.0 mmol) was added in one portion. The solution was allowed to slowly warm up to RT over 3 h. Excess of 10% HCl was added and the reaction mixture was stirred for 20 min. The thiol was extracted with ether, washed with brine, dried over Na2SO4 and concentrated to afford 2.0 g of crude compound 72 which was used in the next step without further purification. 2-(Benzo[b]thiophen-2-ylthio)-1-(3,4-dihydroquinolin-1(2H)-yl)ethanone (73): Crude compound 72 (0.71 g, 4.3 mmol) was dissolved in 40 mL of dry THF under N2, stirred for 30 min at RT and then cooled down to 0° C. NaH (60% in mineral oil, 0.224 g, 5.5 mmol) was added to the ice-cold solution which became a yellowish suspension. The formed suspension was stirred for 40 min at 0° C. and then 2-chloro-1-(3,4-dihydroquinolin-1(2H)-yl)ethanone (0.89 g, 4.3 mmol) was added as a solution in 4 mL of dry THF. The reaction mixture was stirred at RT for 16 h. The work-up, the same as for compound 5, gave crude material which was purified by flash chromatography (CH2Cl2/EtOAc) giving 0.56 g of the crude product. Pumping the crude product under high vacuum over P4O10 at 45° C. for 4 h removed the co-crystallized EtOAc to yield the desired product 73 (36%): MS: m/z+ 340.1 [M+H]+; Anal. Calcd (found) for C19H17NOS2: C, 67.22; (67.18), H, 5.05; (5.11), N, 4.13; (4.08), S, 18.89; (18.70).