Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:35][C:34]=1[NH:48][C:49](=[O:61])[C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][C:51]=1[F:60].O.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:3]=[C:2]([C:37]3[CH:36]=[CH:35][C:34]([NH:48][C:49](=[O:61])[C:50]4[CH:55]=[CH:54][C:53]([C:56]([F:58])([F:59])[F:57])=[CH:52][C:51]=4[F:60])=[C:33]([O:32][CH3:31])[CH:38]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: Nc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 85 °C
Yield: 89.5 %

Procedure:
A mixture of 3-iodo-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.10 g, 0.19 mmol), N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-trifluoromethylbenzamide (0.13 g, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (0.01 g, 0.01 mmol) and sodium carbonate monohydrate (0.06 mg, 0.48 mmol) in water (2 mL) and ethylene glycol dimethyl ether (4 mL) was heated at 85° C. overnight. The solvents were removed under reduced pressure. Water was added into the residue and the mixture was extracted with ethyl acetate three times. The combined organics were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to yield a brown solid which was purified by flash column chromatography on silica using Isco system to provide N1-[4-(4-amino-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-2-fluoro-4-trifluoromethylbenzamide (0.12 g, 0.17 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.89 (dd, 1H), 8.25(d, 1H), 8.28 (s, 1H), 8.00 (t, 1H), 7.94 (s, 1H), 7.88 (d, 1H), 7.73 (d, 1H), 7.24 (m, 15H), 3.90 (s, 3H); MS: MH+ 689.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:32][CH:33]=3)[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-:41].[Ca+2].[Cl-]>C(O)(C(F)(F)F)=O>[ClH:41].[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:32][CH:33]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Cl-]
Reactant: Cc1ccccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)cn1
Agent: [Ca+2]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 1.75 g (3.19 mmol) of (2S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-o-tolylpyridin-3-yl)propanoate in TFA (5.0 mL), protected from the atmosphere by a calcium chloride-filled drying tube was stirred at room temperature for two hours. The reaction mixture was concentrated in vacuo at less than 40° C. and the resulting orange oil was dissolved in 10 mL of ether to which a solution of 5 mL of 1 M HCl/ether was added. The resulting white solid was filtered and washed with ether to give the desired compound as a white powder, 1.65 g, 100% yield.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[CH3:48])=[CH:19][C:18]=2[F:49])[CH2:15][CH2:14]1>O.C(OCC)(=O)C>[CH:13]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[CH3:48])=[CH:19][C:18]=2[F:49])[CH2:14][CH2:15]1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.32 g), sodium hydrogen carbonate (0.52 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(cyclopropyloxy)-3-fluorophenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.15 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-carbonyldiimidazole (0.075 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.070 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.077 g, 45%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CI.[C:13]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: Ic1ccc2[nH]ccc2c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cc(I)ccc21

Procedure:
5-Iodoindole (4.8 g, 20 mmol) was stirred in dry DMF (20 ml) containing MeI (8.5 g, 60 mmol) and K2CO3 (13.8 g, 100 mmol) for overnight at 55° C. The reaction mixture was diluted with EtOAc and passed through celite plug. The illiterate was evaporated to dryness and then oil was further purified by small flash column, Yield (90%). 1H NMR (300 MHz, CDCl3) δ: 3.75 (s, 3H, NMe), 6.39 (d, J=3.0, 1H), 6.98 (d, J=3.0, 1H), 7.07 (d, J=9.0, 1H), 7.44 (dd, J1=9.0, J2=1.2, 1H), 7.93 (d, J=1.2, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].CC#[N:16]>>[C:9]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([NH2:16])=[CH:4][C:5]=1[OH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC#N
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)O
Product: CC(C)(C)c1cc(Cl)c(N)cc1O

Procedure:
2-tert-Butyl-5-amino-4-chlorophenol (C-10) was synthesized following the general scheme above starting from 4-chlorophenol and tert-butanol. Overall yield (6%). HPLC ret. time 3.07 min, 10-99% CH3CN, 5 min run; ESI-MS 200.2 m/z (MH+).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([OH:10])=[CH:8][C:7]=1[OH:13].C([O-])(=O)C.[Na+]>B(F)(F)F.CCOCC>[Cl:5][C:6]1[C:7]([OH:13])=[CH:8][C:9]([OH:10])=[C:11]([C:1](=[O:4])[CH3:2])[CH:12]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)c1cc(Cl)c(O)cc1O
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
Acetic acid (17.5 mL) was added dropwise to a suspension of 4-chlororesorcinol (42.5 g, 0.293 mmol) in boron trifluoride etherate (200 mL) under a nitrogen atmosphere. The reaction mixture was heated at 90° C. for 3.5 hours and then allowed to cool to room temperature. A solid had formed after around 1 hour of cooling. The mixture was poured into 700 mL of a 10% w/v aqueous sodium acetate solution. This mixture was stirred vigorously for 2.5 hours. A light brown solid had formed which was filtered, washed with water and air-dried overnight to afford 1-(5-chloro-2,4-dihydroxy-phenyl)-ethanone (31.6 g, 58%). LCMS: [M-H]+185.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=2[C:19]#[N:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:24]3[CH:25]=[C:26]4[N:33]([CH3:34])[CH2:32][CH2:31][N:27]4[C:28](=[O:30])[N:29]=3)=[CH:13][C:12]=2[C:19]#[N:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2C#N)cc1Cl
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(Cl)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 2-chloro-4-(2-cyano-4-(hydroxymethyl)phenoxy)benzonitrile (60 mg, 0.211 mmol) in THF (S mL), sodium hydride (12.64 mg, 0.316 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (39.1 mg, 0.211 mmol).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:11]([C:17](O)=[O:18])=[C:12]([CH3:16])[NH:13][C:14]=1[CH3:15])=[O:8]>ClCCl>[Cl:3][C:17]([C:11]1[CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:9]([C:7]([O:6][CH3:5])=[O:8])=[C:14]([CH3:15])[NH:13][C:12]=1[CH3:16])=[O:18]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)Cl)C1c1cccc([N+](=O)[O-])c1

Procedure:
Thionyl chloride (0.4 g, 3.4 mmol) was slowly added to a solution of 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1.0 g, 3 mmol) in dichloromethane dropwisely at −25° C. After the completion of the dropwise addition, the reaction was continued under cooling in an ice bath until the solution became clear. After the completion of reaction, the reaction solution was rotary evaporated to dryness to produce a crude product, which was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[N:30]=[C:31]=S.C(O)C.CC(N=C=NC(C)C)C>CN(C=O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[NH:30][C:31]1[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:3]2[C:2]([N:1]=1)=[CH:7][N:6]=[C:5]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([OH:15])[CH2:13][CH2:14]1)[N:4]=2
Reactant: Nc1cnc(N[C@H]2CC[C@H](O)CC2)nc1NC1CCCC1
Reactant: Fc1cccc(F)c1N=C=S
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H]1CC[C@H](Nc2ncc3nc(Nc4c(F)cccc4F)n(C4CCCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-{[5-Amino-4-(cyclopentylamino)pyrimidin-2-yl]amino}trans-cyclohexan-1-ol (1.13 mmol, 330 mg) was dissolved in DMF (8.5 mL) and 2,6-difluorophenyl-isothiocyanate (1.13 mmol, 0.146 mL) was added. The reaction mixture was stirred at room temperature for about 90 minutes. Ethanol (2.5 mL) was added and the reaction mixture was stirred for about an additional 30 minutes. N,N-Diisopropylcarbodiimide (3.40 mmol, 0.532 mL) was added and the reaction mixture was stirred overnight. Solvent was removed and the residue was purified using column chromatography (SiO2, 1:1 n-hexanes/ethyl acetate→ethyl acetate→1% methanol/ethyl acetate) to give the desired product (222.5 mg, 46% yield). ES-MS: 429 (M+1). Tetrahydrofuran can also be used as solvent in this step.
Reaction SMILES: C(N(CC)CC)C.C1(O[C:15](=[O:27])[NH:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]3[CH:26]=2)C=CC=CC=1.Cl.[CH:29]([N:32]1[N:36]=[N:35][C:34]([CH2:37][CH2:38][NH2:39])=[N:33]1)([CH3:31])[CH3:30]>CN1C(=O)CCC1.O>[Br:25][C:22]1[CH:23]=[CH:24][C:19]2[N:20]([CH:26]=[C:17]([NH:16][C:15]([NH:39][CH2:38][CH2:37][C:34]3[N:35]=[N:36][N:32]([CH:29]([CH3:31])[CH3:30])[N:33]=3)=[O:27])[N:18]=2)[CH:21]=1
Reactant: CC(C)n1nnc(CCN)n1
Reactant: O=C(Nc1cn2cc(Br)ccc2n1)Oc1ccccc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)n1nnc(CCNC(=O)Nc2cn3cc(Br)ccc3n2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.15 ml, 1.1 mmol) is added to a stirred mixture of (6-bromo-imidazo[1,2-a]pyridin-2-yl)-carbamic acid phenyl ester (Intermediate B1)(0.30 g, 0.90 mmol) and 2-(2-isopropyl-2H-tetrazol-5-yl)-ethylamine hydrochloride (Intermediate D1)(0.207 g, 1.1 mmol) in NMP (3 ml). The reaction mixture is stirred at 80° C. for 2 hours, cooled and diluted with water (100 ml) resulting in a grey precipitate. The solid is collected by filtration and dried in a vacuum oven to afford the title compound. [MH+ 395.09]
Reaction SMILES: [Cl:1][C:2]([Cl:49])([Cl:48])[CH2:3][O:4][C:5]([N:7]1[C:19]2[CH2:18][N:17]([S:20]([CH2:23][CH:24]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:34][CH2:33]3)[C:25]([O:27]C(C)(C)C)=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].CO>ClCCl>[Cl:49][C:2]([Cl:1])([Cl:48])[CH2:3][O:4][C:5]([N:7]1[C:19]2[CH2:18][N:17]([S:20]([CH2:23][CH:24]([CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:36][CH2:37]3)[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: CC(C)(C)OC(=O)C(CS(=O)(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C(CS(=O)(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 95.4 %

Procedure:
Prepared from 2-[2-(1-benzyloxycarbonyl-piperidin-4-yl)-2-tert butoxy carbonyl-ethanesulfonyl]-1,2,3,4-tetrahydro-β-carboline-9-carboxylic acid 2,2,2-trichloro-ethyl ester (600 mg) to give, after chromatography (SiO2, 2.5% methanol in dichloromethane), the title compound (530 mg, 94%) as a pale yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=O)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[CH:37]1([CH2:40][NH2:41])[CH2:39][CH2:38]1>C1(C)C=CC=CC=1.CO>[CH:37]1([CH2:40][NH:41][C:27](=[O:29])[C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[N:22][C:17]4[N:18]([C:14]([C:11]5([C:7]6[CH:6]=[C:5]7[C:10](=[CH:9][CH:8]=6)[N:1]=[CH:2][CH:3]=[CH:4]7)[CH2:12][CH2:13]5)=[N:15][N:16]=4)[N:19]=3)=[CH:32][CH:31]=2)[CH2:39][CH2:38]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(NCC1CC1)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate (15 mg, 0.036 mmol) in toluene (0.2 mL) was added 2.0 M of trimethylaluminum in toluene (27 μL) at RT followed by addition of cyclopropylmethylamine (5.0 mg, 0.071 mmol). The mixture was stirred at 70° C. overnight. After cooling the mixture was diluted with methanol, and filtered. The filtrate was purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=462.4.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:13]2/[C:9]([N:5]3[CH2:6][CH2:7][CH2:8][C@H:4]3[C:3]([N:2]([CH3:16])[CH3:1])=[O:15])=[N:10][C:11](=[O:14])[S:12]/2)[CH2:24][CH2:23]1
Reactant: CN(C)C(=O)[C@@H]1CCCN1C1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@@H]1CCCN1C1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of N,N-dimethyl-1-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-prolinamide (724 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) in 2-propanol (10 mL) was added piperidinium acetate (436 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (389 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[S:8][C:9](Br)=[CH:10][CH:11]=1.[CH2:13]([Li])[CH2:14][CH2:15][CH3:16]>O>[Br:6][C:7]1[S:8][C:9]([CH:5]([C:4]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:2][CH:3]=2)[OH:1])=[CH:10][CH:11]=1
Reactant: Brc1ccc(Br)s1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Solvent: O
Product: Cc1ccc(C(O)c2ccc(Br)s2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
To an anhydrous tetrahydrofuran (70.0 mL) solution of 2,5-dibromothiophene (5.00 g, 19.6 mmol) was added dropwise n-butyl lithium (2.55 M n-hexane solution, 7.69 mL, 19.6 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 20 minutes at −78° C. p-Tolaldehyde (2.35 g, 19.6 mmol) was then added dropwise and stirred for 10 minutes at −78° C. The reaction mixture was allowed to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5→1:1) to obtain the title compound (4.30 g, 77.5%).
Reaction SMILES: [CH:1]1C=CC=C[CH:2]=1.C([Li])CCC.[CH3:12][O:13][CH:14]([O:21][CH3:22])[C:15](=O)[C:16]#[C:17][CH2:18][CH3:19]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCCCCC>[CH3:12][O:13][CH:14]([O:21][CH3:22])[C:15](=[CH:1][CH3:2])[C:16]#[C:17][CH2:18][CH3:19]
Reactant: c1ccccc1
Reactant: CCC#CC(=O)C(OC)OC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC=C(C#CCC)C(OC)OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyltriphenylphosphonium bromide (24.8 g) is stirred with 100 ml benzene, and 40 ml (1.6 N) butyl lithium in hexane is added over about one-half hour with a water bath used to take up the slight heat of reaction. The mixture (bright orange) is stirred at room temperature for 0.75 hour, and 10.0 g of the 1,1-dimethoxy-3-hexyne-2-one is added dropwise in one-half hour.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].FC(F)(F)S(O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]1[O:15][CH:2]2[CH:3]=[CH:4][C:5]3[C:10]([N:1]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]1=2)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=Cc1ccccc1F
Reactant: c1ccc2ncccc2c1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccccc1C1OC2C=Cc3ccccc3N2c2ccccc21
Yield: 58 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 2-fluorobenzaldehyde (0.095 g, 79 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethane sulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=75/25) of the crude reaction mixture afforded 5-(2-fluorophenyl)-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as inseparable mixture of diastereomers as a white solid (0.118 g, 58% yield, dr determined by 1H NMR analysis of crude reaction mixture is >20:1).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([CH2:18][CH2:19]O)=[C:16]([CH3:21])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:28])CC)C.O>ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([CH2:18][CH2:19][F:28])=[C:16]([CH3:21])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1CCO
Solvent: ClCCl
Solvent: O
Product: Cc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1CCF
Reaction time: 4 h

Procedure:
2.0 g (6.5 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-methyl-5-(2-hydroxyethyl)pyrimidine (Example 33) were dissolved in 30 ml of dichloromethane, and 1.16 g (7.2 mmol) of diethylaminosulfur trifluoride (DAST) were added at -50° C. The mixture was allowed to rise to room temperature, and was subsequently stirred for 4 hours. It was poured into water, the dichloromethane phase was extracted by stirring with sodium hydrogen carbonate solution and the organic extracts were dried and concentrated. Chromatography on silica gel gave 1.55 g (77.6% of theory) of product as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH:17]1([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24](I)[CH:23]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.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>[CH:17]1([NH:20][C:21]([C:22]2[CH:27]=[C:26]([C:6]3[CH:5]=[CH:4][C:3]([C:9](=[O:10])[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:2]([NH2:1])[CH:7]=3)[C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:30])[CH2:18][CH2:19]1
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)c2ccccc2)c(N)c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 48.6 %

Procedure:
To a solution the (2-Amino-4-bromo-phenyl)-phenyl-methanone (276 mg, 1.0 mmol) and N-Cyclopropyl-3-iodo-4-methyl-benzamide (301 mg, 1.0 mmol) in 5 mL of methyl sulfoxide was added potassium carbonate (276 mg, 2.0 mmol) and followed by Pd(PPh3)4 (58 mg, 0.05 mmol). After the reaction mixture was stirred at 95° C. for 4 hours, the reaction mixture was allowed to cool to room temperature and 10 mL of water was added to the mixture. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers washed with water (10 mL) and brine (10 mL), dried over MgSO4, and the solvents were evaporated. The residue was purified by chromatography (hexanes:ethyl acetate=1:1) to give the desired compound as a colorless solid (180 mg, 49%).