Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(N(CC)CC)C.[CH3:19][N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[CH3:19][NH:20][C:21]([NH:11][CH:7]1[C:4]2[CH:5]=[CH:6][S:2][C:3]=2[CH2:10][CH2:9][CH2:8]1)=[O:22]
Reactant: CN=C=O
Reactant: NC1CCCc2sccc21
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)NC1CCCc2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.89 grams (0.01 mole) of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride in 20 ml. of dry benzene is stirred while 1.05 grams (0.01 mole) of triethylamine and 01.7 ml. (excess) of methyl isocyanate are added successively. Addition of the latter gives rise to an exotherm, and the mixture becomes very pasty. The mixture is kept at 45° C. for 1 hour, and after cooling to room temperature, the solid is collected, washed thoroughly with benzene and then with water. On drying, this gives 1.7 grams (81%) of product, melting point 183° C. to 186° C. Recrystallization from acetone gives 1.23 grams, melting point 187.5° C. to 189° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])=[N:12][CH:11]=1)[CH3:9])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:15]3[C:10]([CH:11]=[N:12][C:13]([NH:16][C:17]4[CH:22]=[C:21]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=4[O:28][CH3:29])=[N:14]3)=[C:8]([CH3:9])[N:7]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)c1
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)c1
Yield: 27.9 %

Procedure:
In a similar manner as described for Example 9, 3-bromo-N-[1-(3-{[5-(ethylsulfonyl)-2-methoxyphenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 23) (0.11 g, 0.20 mmol) and 1,2,4-triazole (83 mg, 1.2 mmol) in pyridine (2 mL) and phosphorus oxychloride (0.056 mL, 0.6 mmol) gave 7-(3-bromophenyl)-N-[5-(ethylsulfonyl)-2-methoxyphenyl]-5-methylimidazo[5,1-f][1,2,4]triazin-2-amine (0.028 g) as a yellow solid. 1H NMR (CDCl3): δ8.89 (d, J=2.2 Hz, 1H), 8.85 (s, 1H), 8.69-8.60 (m, 1H), 8.43 (dd, J=1.8, 1.8 Hz, 1H), 7.81-7.75 (m, 2H), 7.63 (dd, J=8.5, 2.3 Hz, 1H), 7.58 (ddd, J=7.9, 2.0, 1.0 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 4.04 (s, 3H), 3.06 (q, J=7.4 Hz, 2H), 2.63 (s, 3H), 1.23 (t, J=7.4 Hz, 3H). MS m/z 502, 504 (M+1, M+3).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:7]2=[O:12].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]1=[O:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CCn1ccc2c(N)cccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCn1ccc2c(NC(=O)c3ccccc3)cccc2c1=O

Procedure:
5-Amino-2-(2-dimethylamino-ethyl)-2H-isoquinolin-1-one (50 mg, 0.0002 mol), benzoyl chloride (36 mg, 0.00026 mol) and N,N-diisopropylethylamine (110 mg, 0.00086 mol) were stirred in methylene chloride (3 mL, 0.05 mol) at room temperature for 2 hours. The mixture was diluted with CH2Cl2 (20 mL) and the organic layer was separated and washed with NaHCO3 (10 mL), dried over Na2SO4, and purified via flash column chromatography (12 g of silica gel, 10% MeOH/CH2Cl2) to give the product as a light yellow solid.
Reaction SMILES: [O-]O.[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:13].CC(C1C=CC=CC=1)=C>>[CH3:10][C:9]([CH3:11])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:13]
Reactant: CC(C)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: C=C(C)c1ccccc1
Agent: [O-]O
Product: CC(C)(O)c1ccccc1

Procedure:
cleaving cumene hydroperoxide in a first stage back mixing reactor in the presence of sulfuric acid and controlling the yield of α-methylstyrene as produced from dimethylphenylcarbinol to no more than 35%, by weight of the reaction mixture output from the first stage,
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].I[CH3:22]>>[CH2:1]([C:5]1[N:6]([CH3:22])[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:17])[F:18])[CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Reactant: CI
Product: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)n1C

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isobutyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 18, 200 mg) by alkylation with iodomethane (110 mg). 4-Isobutyl-3-methyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a colorless oil (140 mg). MS (ESI): 299.2 (MH+).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:29][C:30]([Cl:37])([Cl:36])[CH2:31][O:32][C:33](Cl)=[O:34].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:29][C:30]([Cl:37])([Cl:36])[CH2:31][O:32][C:33]([N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:4][CH2:3]1)=[O:34]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CCC(=C2c3ccccc3Oc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(=C2c3ccccc3Oc3ccccc32)CC1
Temperature: 25 °C

Procedure:
To a mixture of 430 mg (1.55 mmol) of 1-methyl-4-(9H-xanthene-9-ylidene)piperidine [Tetrahedron Letters, 29, 5701 (1988)] and 649 μL (4.65 mmol) of triethylamine in 20 mL of dry toluene at 85° C. under an atmosphere of argon was added over 10 min 1.06 mL (7.7 mmol) of 2,2,2-trichloroethyloxycarbonyl chloride. After 30 min the mixture was cooled to room temperature, poured into a solution of 25% aqueous sodium hydroxide, and was extracted with ethyl acetate (3×). The combined organic portions were dried over sodium sulfate, filtered, and concentrated with vacuo to afford the title compound as a crude oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][NH:13][CH3:14].C1COCC1>O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([N:13]([CH3:14])[CH3:12])=[O:5]
Reactant: CNC
Reactant: O=C(Cl)c1c(F)cccc1I
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c(F)cccc1I
Reaction time: 16 h

Procedure:
2-Fluoro-6-iodobenzoylchloride 1.0 mL, 6.9 mmol was added dropwise to a solution of dimethylamine in THF (2.0 M 7.0 mL, 10 mmol). The reaction mixture was stirred for 16 h and then transferred into water. The resulting suspension was collected by filtration and dried to afford the title compound as a pale yellow solid. The product was used in the next reaction step without further purification. mp 86-89° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)[OH:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11](=[O:16])[C:10](=[O:14])[NH:9]2)=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc(F)c(Br)c1
Product: O=C1Nc2cc(Br)c(F)cc2C1=O
Temperature: 90 °C
Yield: 80 %

Procedure:
To the concentrated sulfuric acid (40 mL) at 50° C. was added N-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide (4 g, 0.0152 mol). The temperature was raised to 90° C. and maintained for 3 h. The reaction mixture was added to ice cold water to get the precipitate. The precipitate was filtered and dried to get the title compound (3.0 g, 80%). LC-MS (ESI): Calculated mass: 243.0; Observed mass: 242.1 [M−H]+ (RT: 0.47 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].Cl[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (770 mg) in DMF (10 mL) was added sodium hydride (60%, 114 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise (2-(chloromethoxy)ethyl)(trimethyl)silane (990 mg) at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 5% aqueous lithium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.90 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:13]>>[C:1]1([CH2:7][C:8]([Cl:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1

Procedure:
Phenylacetic acid (PAA), 0.037 moles (5 g) was heated under reflux with an excess of SOCl2 for 60 minutes at a temperature of 75–80° C. After the reaction was completed, the excess SOCl2 was eliminated by vacuum evaporation, using a water pump (40–50° C.). This process was repeated two to three times, each time adding benzene to aid in elimination of SOCl2 and yielding phenylacetyl chloride (PAC). Then, 0.018 mole of 2-hydrazino-2-imidazoline. HBr (3.5 g) was suspended in ether and shaken with 2N NaOH (2–5 equivalents) on an ice bath, until it was completely dissolved. The PAC was then added dropwise very slowly from a funnel with vigorous shaking. Excess NaOH was present to drive the reaction to completion. After the addition of PAC, the mixture was stirred at 0° C. for an additional 15–30 minutes. The ether layer was washed with water, then with saturated NaHCO3. It was then dried over Na2SO4, filtered and was brought to complete dryness. The solid residue from the ether layer was then crystallized from an ethanol-water mixture (70–80% ethanol). The yield, was approximately 55% without subjecting the residual amide to further separation from the aqueous layer.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](N2C(C)=CC=CC2=O)=O)=[CH:6][CH:5]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH2:20]2)[N:3]=1.CO.[CH2:34]([OH:38])[CH:35](C)[CH3:36].C[O-].[Na+]>O>[CH3:2][C:7]1[N:8]([CH2:9][C:9]2[NH:1][C:2]3=[N:3][C:4]([N:19]4[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)=[O:26])[CH2:20]4)=[CH:5][CH:6]=[C:7]3[N:8]=2)[C:34](=[O:38])[CH:35]=[CH:36][CH:6]=1
Reactant: CC(C)CO
Reactant: Cc1cccc(=O)n1C(=O)Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc(=O)n1Cc1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Into a vial were added (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-methyl-2-oxopyridine-1(2H)-carboxamide (1 equiv) and a solution of methanol and isobutanol (1:1, 1.5 mL). Sodium methoxide (2.0 equiv) was added and the reaction mixture was shaken at 110° C. for 2 h. Water was added and the mixture was extracted with a mixture of methanol/dichloromethane (1:1). The organics were concentrated by Speedvac and the crude material was purified via preparative HPLC to afford the title compound. MS (ES+) (M+H) 421.4; UPLC 1.09 min (Method T).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:25][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][C:35](=[O:37])[CH3:36])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH2:17][NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:21])=[O:20]
Reactant: CC(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1ccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)cc1
Yield: 38.9 %

Procedure:
The title compound (108 mg, 39%, slow crystallizing foam) was prepared from (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylene chloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), and acetyl chloride (0.05 mL, 0.664 mmol) in a manner analogous to the procedure described in Example 40.
Reaction SMILES: [ClH:1].O[CH2:3][CH2:4][NH:5][C:6]1[N:10]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[N:7]=1.[CH:24](O)(C)C>>[ClH:1].[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:1])=[CH:16][CH:15]=1)[CH2:11][N:10]1[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[N:7]2[CH2:24][CH2:3][CH2:4][N:5]=[C:6]12
Reactant: CC(C)O
Reactant: O=C(Cn1c(NCCO)nc2ccccc21)c1ccccc1
Agent: Cl
Product: OC(CN1C2=NCCCN2c2ccccc21)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
Slowly add isopropanolic hydrogen chloride to an isopropanol solution of the base obtained in Step A. Wait for 30 minutes. Suction-filter, and wash with acetone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:25])[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([O-])=O.C([O-])=O.[NH4+]>CO.C1COCC1.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:25])[O:17][CH2:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])OCC1CCCCC1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2cccs2)cc1NC(=O)OCC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
To a stirred solution of cyclohexylmethyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.09 g, 0.25 mmol, 1.0 equiv.) in methanol (5 mL) and THF (5 mL) were added Zn (0.08 mg, 1.25 mmol, 5.0 equiv.) and HCOONH4 (0.13 mmol, 2.0 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 4 h then filtered through celite and concentrated under reduced pressure. The crude residue was diluted with ethyl acetate, washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (silica gel, 30% EtOAc/hexanes) to afford cyclohexylmethyl (2-amino-5-(thiophen-2-yl)phenyl)carbamate (0.08 g, 100% yield). ESI+ MS: m/z 331 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 8.58 (bs, 1H), 7.52 (bs, 1H), 7.33 (d, J=4.5 Hz, 1H), 7.22-7.14 (m, 2H), 7.03 (dd, J=3.5, 5.0 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.11 (s, 2H), 3.89 (d, J=6.5 Hz, 2H), 1.80-1.38 (m, 6H), 1.25-1.03 (m, 3H), 1.03-0.92 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:3]1=2.O.NN>[Pd].C(O)C>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2
Reactant: CN1CCCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCCCc2cc(N)ccc21
Temperature: 60 °C
Yield: 94.6 %

Procedure:
1-Methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (135 mg, 0.66 mmol) in a solution of ethanol (4 mL) and hydrazine hydrate (1 mL) was treated with 10% palladium on carbon (40 mg) and heated at 60° C. for 2 h. The mixture was cooled to room temperature, filtered and concentrated to give 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (110 mgs, 96%) as a grayish oil. 1H-NMR (CDCl3) δ 6.78-6.72 (m, 1H), 6.51 (s, 2H), 3.38 (br s, 2H), 2.82-2.74 (m, 7H), 2.21-2.15 (m, 2H), 1.75-1.68 (m, 2H), 1.57-1.52 (m, 2H); LC/MS (ESI+): 177.16 (M+H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:29]1[CH2:32]C[CH2:30]1)[O:26][CH2:27]C)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.F[C:43](F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(CC1C=C(C(F)(F)F)C=CC=1C=O)C1N=NN(C)N=1.C([Mg]Cl)(C)(C)C.CI>>[CH3:27][O:26][CH:25]([C:16]1[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=1[CH2:14][N:7]([CH2:6][C:5]1[CH:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:35]=[C:3]([C:2]([F:41])([F:40])[F:1])[CH:4]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1)[C:29]([CH3:43])([CH3:32])[CH3:30]
Reactant: CCOC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCC1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Agent: CC(C)(C)[Mg]Cl
Solvent: CI
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C(C)(C)C

Procedure:
The title compound was prepared in an analogous manner to that described for the preparation of (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclobutyl-ethoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)amine from 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde by the addition of tert-butylmagnesium chloride followed by O-methylation with methyl iodide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)[CH:12]([F:14])[F:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:21]=[CH:22][CH:23]=1)[CH:12]([F:13])[F:14]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: N#Cc1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: N#Cc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
EX-576A) A solution of 3-aminobenzonitrile (1.06 g, 9.1 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (2.00 g, 9.01 mmol) was dissolved in 25 mL of dichloroethane and acetic acid (536 mL, 9.37 mmol), then solid NaBH(OAc)3 (2.48 g, 11.7 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3, then dried over MgSO4, and evaporated. The crude product was purified by MPLC on silica gel eluting with 20% to 30% ethyl acetate in hexane to give 1.58 g (54%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzonitrile product as a clear oil. 1H NMR (CDCl3) δ4.38 (s, 3H), 5.89 (dt, 1H), 6.79 (t, 1H), 6.98 (d, 2H), 7.12-7.28 (m, 4H), 7.40(t, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(Oc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, phenol and DBU in THF. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH3:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.CN1C(=O)CCC1>C(N(CC)CC)C>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:25]=[N:26][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH2:30][C:29]5[CH:36]=[CH:37][CH:38]=[CH:39][C:28]=5[CH3:27])=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[N:15]([CH2:20][C:21]([F:24])([F:22])[F:23])[N:16]=1
Reactant: Cc1ccccc1CC1CCCN1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCCC4Cc4ccccc4C)cc2OCC3)n(CC(F)(F)F)n1
Temperature: 160 °C
Yield: 25.2 %

Procedure:
A 10 mL microwave vial was charged with 8-Chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (85 mg, 0.22 mmol) and 2-(2-Methyl-benzyl)-pyrrolidine (231 mg, 6 eq). 0.5 mL of NMP and 0.5 mL of triethylamine was added. The vial was sealed and heated at 160° C. for 24 h. After cooling to room temperature, the solution was purified directly by reverse phase HPLC (0.1% NH4OH/ACN). The isolated solid was further purified by chiral SFC (AD column, 35% MeOH isocratic) to give 27 mg of one enantiomer and 29 mg of 420 (48% total yield). LCMS: 524.2. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 9.08 (s, 1H), 7.92 (s, 1H), 7.27-7.06 (m, 4H), 5.99 (s, 1H), 5.80 (q, J=8.9 Hz, 2H), 4.50 (m, 4H), 4.38 (br s, 1H), 3.49 (t, J=8.6 Hz, 1H), 3.15 (d, J=10.0 Hz, 1H), 2.60-2.53 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 2.10-1.89 (m, 2H), 1.81-1.71 (m, 2H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:33])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24](C4C=NC=CC=4)[CH:25]=3)[NH:20][CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1)C1C=CC=CC=1.FC1C(O)=CC=C(F)C=1C(C1[C:53]2[C:48](=[N:49][CH:50]=[C:51](Cl)[CH:52]=2)NC=1)=O>>[F:33][C:10]1[C:9]([O:8][CH2:1][C:53]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[CH:14][CH:13]=[C:12]([F:15])[C:11]=1[C:16]([C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:17]
Reactant: O=C(c1c(F)ccc(O)c1F)c1c[nH]c2ncc(Cl)cc12
Reactant: O=C(c1c(F)ccc(OCc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Product: O=C(c1c(F)ccc(OCc2cccnc2)c1F)c1c[nH]c2ncccc12

Procedure:
Additional compounds were prepared following the protocol of Scheme 28, replacing pyridin-3-yl-methanol 90 with an appropriate alcohol and optionally replacing (2,6-difluoro-3-hydroxy-phenyl)-(1H-pyrrolo[2,3-b]pyridine-3-yl)-methanone 89 with (2,6-difluoro-3-hydroxy-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)-methanone (prepared as described in Example 11, 3 and 4 of Scheme 8, replacing pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 20 with 5-chloro-1H-pyrrolo[2,3-b]pyridine 4 (see Example 4) in Step 3). The following compounds were made following this procedure:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
5-bromo-2-chloronicotinic acid (8.157 g, 34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.94 g, 36 mmol) were dissolved in DCM (200 ml) and triethylamine (5.3 ml, 38 mmol) and aniline (3.5 ml, 38 mmol) were added. The reaction was stirred under nitrogen overnight at room temperature. More aniline (1.5 ml, 16 mmol) was added the next morning and stirring was continued. When LCMS analysis indicated the formation of the product, the reaction was quenched with water (150 ml). The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were washed with 1N HCl (2×50 ml), saturated sodium bicarbonate (50 ml), and brine (50 ml). They were then combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (˜3 inches, 50:1→30:1 DCM/MeOH). To afford the desired 5-bromo-2-chloro-N-phenylnicotinamide (2.85 g, 9.15 mmol, 26%). MS (ESI pos. ion) m/z: 311 (MH+, 79Br), 313 (MH+, 81Br). Calc'd exact mass for C12H8BrClN2O: 310 (79Br), 312 (81Br).