Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[CH3:19][Si:20]([C:23]#[C:24][CH2:25]Br)([CH3:22])[CH3:21].CN1C(=O)N(C)CCC1>C1COCC1>[C:9]([O:13][C:14]([C:16]1([CH2:25][C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: C[Si](C)(C)C#CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CC#C[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 14.0 ml (2.0 M in THF/n-heptane/ethylbenzene, 28 mmol) LDA in 100 ml THF was treated during 15 min at −78° C. with 2.84 g (20 mmol) cyclopropanecarboxylic acid tert-butyl ester in 20 ml THF. After 6 h at −78° C., a solution of 3-(trimethylsilyl) propargyl bromide and 29 ml DMPU in 40 ml THF was added during 20 min. Over night, the solution was naturally warmed to room temperature, poured on ice/aqueous saturated NH4Cl solution and extracted with ether (three times). The organic phases were washed with aqueous 10% KHSO4, water (5×), aqueous 10% NaCl and dried (Na2SO4) to give 5.59 g of the title compound as volatile dark brown liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][N:12](C=O)C>>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([CH:3]=1)[C:11]#[N:12])=[O:6]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1O
Temperature: 180 °C

Procedure:
To a mixture of 3-bromo-4-hydroxybenzaldehyde (1.00 g, 4.97 mmol) in DMF (10 mL) was added cuprous cyanide (660 mg, 7.46 mmol). The mixture was heated at 180° C. for 8 hours. The solution was filtered off and purified by chromatography on silica gel (PE/EtOAc=8:1) (210 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15](=[O:20])C(F)(F)F)=[CH:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[OH-:21].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([OH:20])=[O:21])=[CH:7][N:8]2[CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of 1-(6-chloro-1-isobutyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (282.7 mg, 0.81 mmol) in a 20% aqueous sodium hydroxide solution (2.7 mL) was heated under reflux for 17 h. At this time, the reaction was cooled to 25° C. and was diluted with water (75 mL). This mixture was extracted with diethyl ether (1×50 mL). The aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-isobutyl-1H-indole-3-carboxylic acid (161.4 mg, 79%) as a cream-colored solid: mp 205-206° C.; EI-HRMS m/e calcd for C13H14ClNO2 (M+) 251.0713, found 251.0713.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:14])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:14])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1ccc(Br)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCC(O)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.9 %

Procedure:
To a solution of ethyl (6-bromopyridin-3-yl)(oxo)acetate (1.00 g) in ethanol (20 mL) was slowly added sodium borohydride (250 mg). The reaction mixture was stirred at room temperature for 4 hr, diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (650 mg, yield 77%) as a colorless oil. MS: 220 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:23])[CH3:22]>>[C:21]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:28][CH:27]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)NCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(C)=O)cc3)ccn2c1=O
Yield: 99.6 %

Procedure:
Methyl 8-(4-(acetamidomethyl)phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (4-(acetamidomethyl)phenyl)-boronic acid (79.3 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (137 mg, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([C:38](=[O:40])[CH3:39])[CH:34]=[C:35]([OH:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:37][C:35]2[CH:36]=[C:31]([Br:30])[CH:32]=[C:33]([C:38](=[O:40])[CH3:39])[CH:34]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CC(=O)c1cc(O)cc(Br)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(C)=O)c2)c1CCC(=O)OCC
Yield: 79.3 %

Procedure:
A similar procedure as described in Example 43, step 3 was used, starting from 4-[3-[6-bromo-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.36 g, 5.0 mmol), 1-(3-bromo-5-hydroxy-phenyl)-ethanone (965 mg, 4.48 mmol), and potassium carbonate (1.38 g, 10 mmol) to afford 4-[3-[6-(3-acetyl-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.15 g, 79%) as a colorless viscous oil: EI(+)-HRMS m/e calcd for C31H41BrO7 (M+Na)+ 627.1928. found 627.1925.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[C:23]([CH3:33])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([N:30]([CH3:31])[CH3:32])=[O:29])=[C:23]([CH3:33])[CH:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Cc1cc(O)ccc1CC(=O)N(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)ccc1CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (90 mg, 0.319 mmol) was dissolved in toluene (1 ml) and 2-(4-hydroxy-2-methylphenyl)-N,N-dimethylacetamide (62 mg, 0.319 mmol), triphenylphosphine (126 mg, 0.479 mmol), and DIAD (93 μl, 0.479 mmol) added and the mixture stirred at RT overnight. The mixture was concentrated in vacuo and the residue purified by chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 10-100% water:acetonitrile+0.1% TFA to afford the title compound. LC/MS (m/z): 457 (M+H)+. GPR119 Human EC50: 1.7 nM.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]2[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1>O1CCCC1>[Br:33][C:29]1[CH:28]=[C:27]([NH:26][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:8](=[O:11])[CH:9]=[CH2:10])[CH:15]=3)[N:20]=[CH:19][C:18]=2[C:24]#[N:25])[CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 250 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and acryloyl chloride (0.321 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 250° C., volatile material was removed and the residue was slurried with water and collected. Recrystallization from ethanol gave 0.580 g of brown solid: mass spectrum (electrospray, m/e): M+H 393, 395.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH:29]=O)=[CH:23]3)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.N1CCCCC1>C(O)C>[N:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH:29]=[C:3]2[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]2=[O:10])=[CH:23]3)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
A mixture of 2-oxindole (29 mg, 0.22 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (60 mg, 0.22 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 81 mg (95%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([N:42]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:42])=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.2 %

Procedure:
A mixture of 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylic acid (0.25 g), 1-hydroxybenzotriazole ammonia complex (0.11 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxamide as colorless crystals (0.23 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 160-161° C.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:17]([O:19][C:20](=[O:39])[C:21]([N:23]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH3:18]>>[CH2:17]([O:19][C:20](=[O:39])[C:21]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=2)=[CH:34][CH:33]=1)=[O:22])[CH3:18]
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(N)cc1
Product: CCCCCCOc1ccc(C(=O)Nc2ccc(CN(Cc3ccccc3)C(=O)C(=O)OCC)cc2)cc1
Yield: 58 %

Procedure:
The same procedure as employed in the preparation of Example 15, step d but using 4-hexyloxy-benzoyl chloride and ethyl[(4-aminobenzyl)(benzyl)amino](oxo)acetate gave the title compound as a colorless oil (58%). M−(ESI): 515.2. HPLC (Condition A), Rt: 6.0 min (HPLC purity: 94.9%).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:3]2[N:4]3[C:5]4[CH:18]=[CH:17][CH:16]=[N:15][C:6]=4[NH:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[C:10]3=[N:1][N:2]=2)=[CH:24][CH:23]=1
Reactant: OCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)methanol (300 mg, 0.88 mmol) in dichloromethane (10 mL) was added thionyl chloride (excess, 1 mL) and the resulting solution was stirred at room temperature for 1 hour. The volatiles were removed in vacuo and the residue was carefully neutralized with a solution of sodium bicarbonate. The mixture was extracted with dichloromethane (3×25 mL) and the combined organics were dried over sodium sulfate, concentrated in vacuo. The 3-(4-(chloromethyl)phenyl)-9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepine was obtained as a yellow solid (317 mg, quantitative). M.p.=260-262° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.79 (s, 1H), 8.20 (dd, J=4.8, 1.6 Hz, 1H), 7.94 (dd, J=8.0, 1.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.45-7.39 (m, 3H), 7.35-7.31 (m, 1H), 7.16-7.10 (m, 2H), 6.90 (dd, J=7.6, 4.8 Hz, 1H), 4.81 (s, 2H); LCMS [M+H]: 360.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: CN(C)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI/CI): predicted mass C19H22N6O2, 366.2.
Reaction SMILES: COC(C1SC(C)=CC=1)=O.BrN1C(=O)CCC1=O.[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([CH:28](Br)[Br:29])=[CH:26][CH:27]=1)=[O:22]>C(Cl)(Cl)(Cl)Cl>[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][Br:29])=[CH:26][CH:27]=1)=[O:22]
Reactant: COC(=O)c1ccc(C(Br)Br)s1
Agent: COC(=O)c1ccc(C)s1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)s1
Yield: 25 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid methyl ester (20.0 g, 0.13 mol) was dissolved in a suspension of N-bromosuccinimide (45.4 g, 0.26 mol) and 2,2′-aza-bis-isobutyronitrile (0.1 g, 0.61 mmol) in 1 L of carbon tetrachloride. The suspension was refluxed for 48 hours then cooled and the precipitate was filtered off. The filtrate was concentrated and the residue was purified on silica gel (100% hexanes then 9:1 Hexanes-Ethyl acetate) to provide a 26 g fraction containing mainly the di-brominated compound 5-dibromomethyl-thiophene-2-carboxylic acid methyl ester as a yellow oil and a more polar fraction (7.5 g) containing mainly compound T-1 (25% yield) as a yellow oil (70% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.O[CH2:56][CH2:57][N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.[CH3:64][S:65]([OH:68])(=[O:67])=[O:66]>C1COCC1.C(Cl)Cl>[CH3:64][S:65]([OH:68])(=[O:67])=[O:66].[CH3:64][S:65]([OH:68])(=[O:67])=[O:66].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:56][CH2:57][N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: OCCN1CCOCC1
Reactant: COc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CS(=O)(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2cc1OCCN1CCOCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-(6-chloro-2,3-dihydro-indol-1-yl)-6-methoxy-quinazolin-7-ol (200 mg, 0.610 mmol; from Example 70) and triphenylphosphine(160 mg, 0.610 mmol) in dry THF (3 mL) under N2(g) was added diethyl-azodicarboxylate (106 μL, 0.671 mmol) dropwise at 0° C. over 10 minutes followed by a solution of 4-(2-hydroxyethyl)-morpholine (81 μL, 0.671 mmol) in dry THF (0.8 mL). The mixture was allowed to warm to 20° C. and stirred 16 hours before quenching with H2O (20μL) and concentrating in vacuo. Flash chromatography of the residue on silica using first 45% acetone/CH2Cl2 followed by 10% MeOH/CH2Cl2 eluted the product as its free-base (180 mg), which was precipitated as its bis(methanesulfonate) salt by addition of 2.0 eq. of methanesulfonic acid to a solution in CH2Cl2. (M.P. 150°-158° C. (dec); LC-MS: 441 (MH+); anal. RP18-HPLC RT: 3.76 min.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:31])[N:23]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[N:24]1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:26]=[CH:27][N:23]([CH:22]([F:31])[F:21])[N:24]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccn(C(F)F)n1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccn(C(F)F)n3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 1-difluoromethyl-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=432.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C:9]1([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2.20 g of 2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in 50 ml DCM was added 1.15 ml of benzaldehyde, followed by the addition of 2.61 g of sodium triacetoxyborohydride in small portions. The reaction was stirred at r.t. overnight. To the reaction was then added water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. 3.30 g (100%) of the title compound were obtained and used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH:19]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)C1CCCCC1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with cyclohexanesulfonyl chloride to obtain the desired product. 1H NMR (300 MHz, CDCl3): δ 7.43 (dd, J=1.5 & 10.2 Hz, 1H), 7.37 (ddd, J=2.4, 4.8 & 9.6 Hz, 1H), 7.27 (m, 1H), 7.11 (dd, J=9.3 & 18.0 Hz, 1H), 6.64 (br s, 1H), 6.18 (dt, J=1.5, 9.0 & 17.4 Hz, 1H), 5.63 (br s, 1H), 2.95 (triplet of triplet, 2.10-1.16 (m, 10H); m/z=509 [M−1]−.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C([O:15]O)(C)(C)C.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:8][C:7]1[C:6](=[O:15])[CH:5]=[C:4]([CH3:9])[C:3](=[O:10])[C:2]=1[CH3:1]
Reactant: CC(C)(C)OO
Reactant: Cc1ccc(C)c(O)c1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 93 %

Procedure:
A solution of 13.6 g (100 mmol) of 2,3,6-trimethylphenol in 40 ml of acetic acid and a solution of 32.3 g (250 mmol) of 70% by weight aqueous tert-butyl hydroperoxide in 20 ml of acetic acid were simultaneously added dropwise to a stirred solution of 0.68 g (2.0 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene and 0.5 ml of concentrated sulfuric acid in 50 ml of acetic acid at 40° C. with cooling. The reaction mixture was then subjected to steam distillation. The distillate was extracted by shaking with methylene chloride. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and concentrated to a yellow oil, which slowly solidifed. 14.0 g (93%) of 2,3,5-trimethyl-p-benzoquinone were obtained in the form of yellow oily crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[NH:11][CH:10]=1.I.CS[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23].N.[ClH:30]>CO.CCOCC.C(O)C>[ClH:30].[ClH:30].[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[NH:23])[CH:16]=2)[NH:11][CH:10]=1
Reactant: CN1CCC[C@H]1CCc1c[nH]c2ccc(N)cc12
Reactant: CSC(=N)c1cccs1
Agent: Cl
Agent: I
Agent: N
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: CN1CCC[C@H]1CCc1c[nH]c2ccc(NC(=N)c3cccs3)cc12
Reaction time: 0.5 h

Procedure:
To an argon purged round bottom flask was charged 146 (40 mg, 0.164 mmol) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (94 mg, 0.329 mmol) followed by absolute ethanol (3 mL). The reaction was stirred using a magnetic stirbar for 60 hours at room temperature. TLC (10% 2 M ammonia in methanol/90% dichloromethane) revealed all starting amine had reacted. The reaction as treated with ether (50 mL). The resulting yellow precipitate was collected by vacuum filtration and washed with ether. The precipitate was washed from the filter using methanol. The residue was concentrated, and purified by silica gel column chromatography (5-10% 2M ammonia in methanol/95-90% dichloromethane) to afford a yellow oil. The purified product was dissolved in anhydrous methanol (3 mL) and treated with 1M hydrogen chloride in ether (5 mL). After stifling for 30 minutes the precipitate was collected by vacuum filtration. The precipitate was washed with ether, followed by washing from the filter with methanol. The filtrate was concentrated and dried under high vacuum. Yield: 21 mg of yellow solid, compound 147 (30%) Melting point 212° C. 1H NMR (MeOD-d3) δ 8.09 (br s, 2H), 7.76 (s, 1H), 7.59 (d, 1H, J=8.7 Hz), 7.41 (br s, 1H), 7.35 (s, 1H), 7.19 (d, 1H, J=8.7 Hz), 3.67 (br m, 1H), 3.19 (br m, 1H), 3.1-2.8 (br m, 2H), 2.91 (s, 3H), 2.46 (br m, 2H), 2.2-1.8 (br m, 5H). MS (TOF+): Exact calc. for C20H25N4S 353.1794 (MH+). found 353.1782.