Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:24][N:25]([CH2:27][CH2:28]CCl)[CH3:26].O.[CH3:32]N(C=O)C>>[CH3:24][N:25]([CH3:26])[CH:27]([CH3:28])[CH2:32][N:13]1[CH2:12][CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:6]2[C:14]1=[O:15]
Reactant: CN(C)C=O
Reactant: CN(C)CCCCl
Reactant: O=C1NCCn2c1c(-c1ccccc1)c1cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(CN1CCn2c(c(-c3ccccc3)c3cc(Cl)ccc32)C1=O)N(C)C
Temperature: 50 °C

Procedure:
A solution of 4.5 grams (0.015 mole) 8-chloro-10-phenyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-1-one in 30 ml DMF, is added to a suspension of sodium hydride (1 gram of 50% dispersion, 0.02 mole) in 20 ml DMF. After stirring at 34°-40° C. for 20 minutes a solution of freshly distilled dimethylaminopropyl chloride (1.8 grams, 0.015 moles) in 5 ml DMF is added dropwise. Stirring is continued and the reaction mixture is heated at 50° C. for 8 hours. The mixture is cooled, and poured into cold water (300 ml). This is extracted 5 times with methylenedichloride. The extracts are washed well with saline. After drying the extract over sodium sulfate, the drying agent is filtered off and the filtrate is concentrated. The residue is diluted with ether. The product crystallizes out and is filtered off. Recrystallization from heptane gives 3.4 grams (62%) of above titled product, m.p. 151°-52° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]([NH2:21])=O)=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)C(C)C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]#[N:21])=[C:13]([C:15]([F:17])([F:18])[F:16])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(N)=O)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C#N)s1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
2-(N-BOC-Aminomethyl)-4-trifluoromethylthiazole-5-carboxamide [sic] (4.6 g, 14.14 mmol) was dissolved in dichloromethane (30 ml) and cooled to −5° C. Ethyldiisopropylamine (4.6 g, 35.35 mmol) and a solution of trifluoroacetic anhydride (3.4 g, 16.26 mmol) in dichloromethane (10 ml) were added at this temperature. Then, the mixture was stirred for a further 2 hours at 0° C. It was washed in succession with saturated sodium hydrogen carbonate solution and 5% strength citric acid solution. After drying (MgSO4), the solvent was removed on a rotary evaporator. The crude product was extracted by stirring with diethyl ether/petroleum ether. The supernatant was separated from the oil and concentrated on a rotary evaporator. Yield: 1.9 g (6.18 mmol, 44%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[NH:45]1[CH2:50][CH2:49][CH:48]([C:51]2[C:52](=[O:61])[NH:53][C:54]3[C:59]([CH:60]=2)=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:47][CH2:46]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:45]2[CH2:46][CH2:47][CH:48]([C:51]3[C:52](=[O:61])[NH:53][C:54]4[C:59]([CH:60]=3)=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH2:49][CH2:50]2)=[O:34])[CH2:18][CH2:17]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Triethylamine (5.0 μL, 0.035 mmol) was added to a solution of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (12.0 mg, 0.035 mmol) and 4-nitrophenyl chloroformate (7.0 mg, 0.035 mmol) in tetrahydrofuran (3 mL) at 0° C. After 20 min, 3-piperidin-4-ylquinolin-2(1H)-one (8.0 mg, 0.035 mmol) and triethylamine (15 μL, 0.11 mmol) were added and the mixture allowed to warm to ambient temperature. After 1 h, saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane (3×). The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→93% dichloromethane/methanol) gave the title compound (17 mg). MS 600.2340 (M+1).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[N:28][O:29][CH3:30])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Cl.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.O1CCOCC1>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][O:29][CH3:30])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=NOC)c4)cc23)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNOC)c4)cc23)CC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 34.6 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)imino]methyl}phenyl)-1H-indole-7-carboxamide (58 mg, 0.123 mmol) in DCM (3.0 mL) and MeOH (3.0 mL) was added HCl in 1,4-dioxane to maintain pH=4 at 0° C. Sodium cyanoborohydride (176 mg, 3.69 mmol) was then added and stirred overnight for 48 h. The compound was purified by Gilson Preparatory HPLC to give 20.0 mg of the title compound (89%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](O)=[N:8]2.[C:14](=O)([O-])[O-:15].[K+].[K+].CI.O>CN(C=O)C>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]([O:15][CH3:14])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: OCc1cccc2nc(O)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(CO)c2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
5-(Hydroxymethyl) quinolinol (6.7 g, 38 mmol) was dissolved in DMF (38 mL) and treated with potassium carbonate (16 g, 116 mmol) followed by methyl iodide (2.9 mL, 6.8 g, 48 mmol). The mixture was allowed to stir overnight at RT, then poured into a separatory funnel with water and extracted 3× DCM. The organic layer was dried over Na2SO4, and concentrated to give solid 5-hydroxymethyl-8-methoxyquinoline (6.5 g). 1H NMR (CDCl3) δ 8.97 (d, 1H), 8.51 (d, 1H) 7.49 (m, 2H), 6.99 (d, 1H), 5.05 (s, 2H), 4.09 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](Cl)=[O:14].[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: Nc1ccnc2cc(C(F)(F)F)ccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1C(=O)Nc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 70 °C
Yield: 55.8 %

Procedure:
5-Methyl-3-phenylisoxazole-4-carbonyl chloride (100 mg) and 4-amino-7-trifluoromethylquinoline (250 mg) were dissolved in dichlorormethane (5 mL) and pyridine (0.3 mL). The reaction solution was heated at 70° C. overnight and then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), dried, evaporated and purified by flash column chromatography (EtOAc/hexanes=1/6) to give 5-methyl-3-phenyl-N-(7-trifluoromethyl-4-quinolinyl)-4-isoxazolecarboxamide (100 mg) as a white solid. 1H NMR (CDCl3): δ 2.91 (s, 3H), 7.33-7.69 (m, 9H), 8.39 (s, 1H, NH), 8.99 (d, J=5.1 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ-63.26; LCMS: ret. time: 34.04 min.; purity: 98.90%; MS (m/e): 398.77 (MH+).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](Cl)(=[O:11])[O:8][CH2:9][CH3:10].[OH-].[K+]>C(OCC)C>[C:7](=[O:11])([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[O:8][CH2:9][CH3:10]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCOC(=O)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
In a flask (5-liter volume), 2,2,2-trifluoroethanol (800 g, 8.0 mol), ethyl chlorocarbonate (867 g, 8.0 mol) and diethyl ether (1000 ml) were charged. While the flask was cooled so that the reaction was carried out at -5° C. to 0° C., a 29.5% by weight aqueous solution of potassium hydroxide (1500 g) was added dropwise to the flask for 6 hours and the mixture was stirred for 12 hours at room temperature. The ether layer was separated, washed with water, dried and distilled to give ethyl 2,2,2-trifluoroethyl carbonate as a colorless liquid (960 g, yield 70%). The chemical structure of the produced compound was determined based on the IR and NMR absorbance spectra shown in FIG. 5 and FIG. 6 respectively and the mass spectrometry spectrum (M/e: 172).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)#[CH:2].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].[CH2:32]([OH:34])[CH3:33]>>[C:25]([O:11][C@@H:10]1[C@@H:12]([CH2:13][O:14][C:32](=[O:34])[CH3:33])[O:15][C@@H:8]([N:7]2[CH:16]=[C:3]([C:1]#[CH:2])[C:4](=[O:18])[NH:5][C:6]2=[O:17])[CH2:9]1)(=[O:27])[CH3:26]
Reactant: C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#Cc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](COC(C)=O)O2)c(=O)[nH]c1=O
Yield: 92 %

Procedure:
5-ethynyl-2'-deoxyuridine (J. Med. Chem., 26(5), 661-6, (1983)) (1.26 g, 5.0 mmole), 10 ml of dry pyridine, and 1.22 g of acetic anhydride (12.0 mmole) were stirred together at room temperature for 20 hr. The resulting clear solution was evaporated to give a syrupy residue which upon co-evaporation with ethanol gave a white solid. Re-crystallisation from ethanol gave 1.49 g (92%) of the title compound as white crystals melting at 152°-4° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.O>C(OCC)(=O)C>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:1](=[O:3])[CH3:2])=[CH:15][CH:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccc(F)cc1
Reaction time: 12 h
Yield: 102.5 %

Procedure:
Step b) Add acetyl chloride (9.28 g, 118 mmol) to a mixture of triethylamine (16.0 g, 158 mmol) and 4-fluorobenzylamine (9.90 g, 78.8 mmol) in 200 mL of ethyl acetate at 0° C. and stir for 12 hours. Add 100 mL of water to the mixture. Extract aqueous layer with ethyl acetate (3×100 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4 Remove solvent under reduced pressure to give N-(4-fluorobenzyl)acetamide (13.5 gm) in 100% yield as a yellow oil. Add NaH (6.5 g, 162 mmol) to N-(4-fluorobenzyl)-acetamide (13.5 g, 80.8 mmol) in 200 mL of tetrahydrofuran at 0° C. and stir for 4 hours. Then add methyl iodide (22.9 g, 161.6 mmol) to the above mixture and stir for 12 hours. Pour mixture into 200 mL of water. Extract aqueous layer with methylene chloride (3×200 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4. Remove solvent under reduced pressure. Purify the residue by column chromatography (silica gel, 5% acetone in hexanes, 50% acetone in hexanes) to give N-(4-fluorobenzyl)-N-methylacetamide (9.1 gm) in 64% yield as a yellow oil. Add Lawesson reagent (20.3 g, 50.3 mmol) to N-(4-fluorobenzyl)-N-methylacetamide (9.1 g, 50.3 mmol) in 200 mL of toluene and heat to 100° C. for three hours. Remove solvent under reduced pressure. Purify the residue with a column chromatography (silica gel, 2% methylene chloride in hexanes, 100% methylene chloride) to give N-(4-fluorobenzyl)-N-methylthioacetamide (5.6 g) 56.5% as a yellow solid: MS 198 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([C:16]#[C:17][CH:18]3[CH2:20][CH2:19]3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:21]=1.[C:22]12([CH3:34])[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]2[C:31](Cl)=[O:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:31]([CH:23]3[CH2:24][CH:25]4[C:28]([CH3:30])([CH3:29])[C@@:22]3([CH3:34])[CH2:27][CH2:26]4)=[O:32])[C:9](=[O:11])[O:8][C:7]([C:16]#[C:17][CH:18]3[CH2:20][CH2:19]3)([C:12]([F:13])([F:14])[F:15])[C:6]=2[CH:21]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(C(=O)N1C(=O)OC(C#CC3CC3)(C(F)(F)F)c3cc(Cl)ccc31)C2
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 39.6 %

Procedure:
To a solution containing (+) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (12.97 g, 0.041 mol), 4-dimethylaminopyridine (1.02 g, 0.0083 mol), and (-) camphanic acid chloride (14.22 g, 0.06556 mol) in 350 mL of dry dichloromethane, stirred under argon in an ice bath, was added triethylamine (22.84 mL, 0.164 mol). The cooling bath was removed and the reaction was allowed to proceed at room temperature. After 75 min. the reaction was judged complete by thin layer chromatography (SiO2, 4% EtOAc in CHCl3), and the solution was diluted with 500 mL of CHCl3 then washed with 10% citric acid (2X), water (1X), and brine (1X). Drying (MgSO4), filtration, and removal of the solvent in vacuo left a colorless foam. This material was triturated with 200 mL of boiling hexane. On cooling to room temperature the desired diastereomeric camphanate imide precipitated. The solid was collected on a frit, washed with a little cold hexanes and dried in vacuo to give 7.79 g of 6-chloro-1-(1S)-camphanoyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as white crystals. mp: 164°-165° C. HPLC purity: 99.2% @254 nm. 1H-NMR (CDCl3): δ0.77 (s, 3H), 0.86-0.96 (m, 4H), 1.08 (s, 3H), 1.19 (s, 3H), 1.44 (m, 1H), 1.76 (m, 1H), 1.95 (m,1H), 2.51 (m, 2H), 7.42 (dd, J=2.4,9.0 Hz, 1H), 7.63 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:16])[CH3:2].[C:18]1([S:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)C=O)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)[CH3:36].C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:36][C:28]2[C:27]([S:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:25])=[O:26])=[N:34][CH:33]=[CH:32][CH:29]=2)=[C:7]1[CH3:16])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccnc(S(=O)(=O)c2ccccc2)c1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
A solution of (5-fluoro-2-methyl-indol-1-yl)-acetic acid ethyl ester (0.95 g, 4.04 mmol), prepared as described in Example 1 of WO/2006/092579, and 2-(benzenesulfonyl)isonicotinaldehyde (1.0 g, 4.04 mmol) in dry dichloromethane (45 ml) was added slowly over 5 minutes to a stirred solution of TMSOTf (1.46 ml, 8.08 mmol) in dry dichloromethane (12.5 ml) cooled to 0° C. under N2. This mixture was stirred for 15 minutes and triethylsilane (1.94 ml, 12.12 mmol) was added in one portion. The reaction mixture was stirred for 2 h 30 minutes, warmed to room temperature, and quenched by the slow addition of saturated aqueous NaHCO3 (10 ml). The resulting biphasic mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate:hexanes 0:100 to 60:40 v/v to afford 1.21 g (64%) of the title compound (LCMS RT=6.63 min, MH+466.8).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[CH:8]([N:11]1[C:15]([C:16]2[N:17]=[C:18]3[C:24]4[CH:25]=[CH:26][C:27]([C:29]5[NH:33][C:32]([CH3:34])=[N:31][CH:30]=5)=[CH:28][C:23]=4[O:22][CH2:21][CH2:20][N:19]3[CH:35]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].IC>C1COCC1.O>[CH3:3][N:31]1[CH:30]=[C:29]([C:27]2[CH:26]=[CH:25][C:24]3[C:18]4[N:19]([CH:35]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:17]=4)[CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)[N:33]=[C:32]1[CH3:34]
Reactant: Cc1ncc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a 100 mL round bottom flask charged with NaH (12 mg, 0.5 mmol) was added DMF (6 mL) dropwise, followed by 271 (100 mg, 0.25 mmol). After stirring for about 1 hour, iodomethane (48 mg, 0.33 mmol) was added dropwise at 0° C. in THF. Then the mixture was allowed to warm up to room temperature slowly and stirred for 2 hours. The reaction mixture was poured into water, extracted with EtOAc, the organic phase was dried over anhydrous Na2SO4, concentrated, then purified by pre-TLC (EtOAc) to give 50 mg (52% Yield) of 282. 1H NMR (CDCl3, 400 MHz): δ8.48 (d, J=8.0 Hz, 1 H), 7.87 (s, 1 H), 7.64 (s, 1 H), 7.48-7.44 (m, 2 H), 7.14 (s, 1 H), 6.04-5.98 (m, 1 H), 4.51-4.43 (m, 4 H), 3.62 (s, 3 H), 2.45 (s, 3 H),1.60 (d, J=6.8 Hz, 6 H), and 15 mg (16% yield) of the regioisomer 9-(1,2-dimethyl-1H-imidazol-5-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 291 1H NMR (CDCl3, 400 MHz): δ8.57 (d, J=8.0 Hz, 1 H), 7.87 (s, 1 H), 7.87 (s, 1 H), 7.69 (s, 1 H), 7.16 (d, J=6.8 Hz, 1 H), 7.06-7.04 (m, 2 H), 6.02-5.96 (m, 1 H), 4.54-4.52 (m, 2 H), 4.48-4.47 (m, 2 H), 3.59 (s, 3 H), 2.46 (s, 3 H),1.60 (d, J=6.8 Hz, 6 H). LC-MS: m/z=389 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[C@:13]([CH2:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)([CH3:16])[N:12]3[CH:26]=[CH:27][N:28]=[C:11]23)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[Al].[I:30]N1C(=O)CCC1=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[C@:13]([CH2:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)([CH3:16])[N:12]3[C:26]([I:30])=[CH:27][N:28]=[C:11]23)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2nccn21
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Al]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(I)n21
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A flask containing a solution of 4-[(R)-1-(3,5-dichloro-4-fluoro-phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-3-ylmethyl]-benzonitrile (48.8 g, 117 mmol) in CH2Cl2 (900 mL) was covered with aluminum foil and partially submerged in an ice water bath. To this solution was added a solid mixture of N-iodosuccinimide (29.1 g, 129 mmol) and pyridinium p-toluenesulfonate (2.95 g, 11.7 mmol) in four separate portions over a 30 min period. The reaction was allowed to stir in the thawing ice bath for 1 h and then the bath was removed. Stirring was continued overnight. Saturated aqueous Na2S2O3 (300 mL) was added to the reaction and the mixture was transferred to a separatory funnel using CH2Cl2 (200 mL) and water (1 L). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×500 mL) and EtOAc (500 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give a yellow oil. This oil was purified by flash chromatography on silica gel (0-2.5% EtOAc/toluene) to give 52 g of the title compound as a white solid, m/z 541.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])[CH2:11][C:10]=12)=[O:4].[CH3:26]OC(C1C=C(O)C=C2OC(C)(C)CC=12)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][C:12]([CH3:26])([CH3:14])[CH2:11][C:10]=12)=[O:4]
Reactant: COC(=O)c1cc(O)cc2c1CC(C)(C)O2
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)(C)O2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 6-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (197e). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=9.09 Hz, 2 H) 7.17 (d, J=2.27 Hz, 1 H) 7.10 (d, J=8.84 Hz, 2 H) 6.64 (d, J=2.02 Hz, 1 H) 3.89 (s, 3 H) 3.35 (s, 2 H) 3.06 (s, 3 H) 1.52 (s, 6 H); LCMS for C19H20O5S m/z 377.20 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([N:21]1[C:25]([C:26]#[N:27])=[C:24]([CH:28]=O)[N:23]=[C:22]1[N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)[C:18]#[C:19][CH3:20].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([N:21]1[C:25]([C:26]#[N:27])=[C:24]([CH:28]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:23]=[C:22]1[N:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]1)[C:18]#[C:19][CH3:20]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C#N
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=CC(=O)OCC)c1C#N
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
0.038 g of sodium hydride was added to a 5 ml tetrahydrofuran solution of 0.243 g of ethyl diethylphosphonoacetate at 5° C. under a nitrogen atmosphere. 0.310 g of t-butyl 4-[1-(2-butynyl)-5-cyano-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate dissolved in 5 ml of tetrahydrofuran was added, and the mixture was stirred for 30 minutes. 50 ml of ethyl acetate and 25 ml of 0.1N sodium hydroxide were added to the solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.380 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3:7).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][C:28](=[O:34])[NH:27][C:26]=2[CH:35]=1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[C:31]([CH3:32])([CH3:33])[CH2:30][CH2:29][C:28](=[O:34])[NH:27][C:26]=3[CH:35]=2)=[N:3][CH:4]=1
Reactant: N#CCOc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Product: CC1(C)CCC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCC#N)n3)ccc21

Procedure:
The title compound was prepared from [2-(2,5-dichloropyrimidin-4-ylamino)-3-fluorophenoxy]-acetonitrile and 8-amino-5,5-dimethyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one in an analogous manner to Example 927 to afford a yellow foam (37 mg, 48%). Mp: 142-8° C. LCMS (m/e) 481 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.52 (m, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 7.21 (d. J=8 Hz, 1H), 7.08 (m, 1H), 6.96 (d, J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 6.55 (s, 1H), 4.79 (s, 2H), 2.37 (m, 2H), 2.10 (m, 2H), 1.36 (s, 6H).