Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]([CH3:13])([CH3:12])[C:10]2[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=2[CH2:4][C@H:3]1[O:17][CH3:18].O=[CH:20][CH2:21][CH2:22][NH:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25].C(O)(C(F)(F)F)=O>>[CH:26]1([C:24]([NH:23][CH2:22][CH2:21][CH2:20][NH:1][C@@H:2]2[C:11]([CH3:13])([CH3:12])[C:10]3[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=3[CH2:4][C@H:3]2[O:17][CH3:18])=[O:25])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=CCCNC(=O)C1CCCCC1
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1N
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NCCCNC(=O)C1CCCCC1

Procedure:
Following the process of Example 11(c) using (6R,7R)-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide and cyclohexanecarboxylic acid (3-oxo-propyl)-amide the TFA salt of the title compound was prepared. (m/z): [M+H]+ calcd for C24H37N3O3, 416.28; found, 416.5.
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[OH:8][CH:9]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][N:11]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:37])[C@H:29]([C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[OH:30])=[CH:23][CH:22]=1)C(=O)OC(C)(C)C>>[ClH:7].[ClH:7].[OH:8][CH:9]([CH2:38][O:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:10][NH:11][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:37])[C@H:29]([C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[OH:30])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(NC(=O)[C@@H](O)c2csc(N)n2)cc1)CC(O)COc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1nc([C@H](O)C(=O)Nc2ccc(CCNCC(O)COc3ccccc3)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 ml of a 4N hydrogen chloride-ethyl acetate solution was added to 10 ml of a methanolic solution of 285 mg of t-butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-[2-[4-[[2-(2-aminothiazol-4-yl)-2-hydroxyacetyl]amino]phenyl]ethyl]carbamate at room temperature. The reaction mixture was stirred at room temperature for four hours. The solvent was evaporated off and the residue was purified by means of silica gel column chromatography (eluate: chloroform/methanol=7/1) to obtain 222 mg of (S)-4′-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethyl]-2-(2-aminothiazol-4-yl)-2-hydroxyacetanilide dihydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:13])[CH2:11]O)[CH3:2].CCOCC.P(Br)(Br)[Br:22]>N1C=CC=CC=1.CCCCCC>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:13])[CH2:11][Br:22])[CH3:2]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)CO
Reactant: BrP(Br)Br
Solvent: CCCCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)C=C(C)C=CC=C(C)CBr
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
36.5 g. of 8-hydroxy-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl ester are dissolved in 380 ml. of ether. The solution is cooled to 0° C., and after the addition of 3 drops of pyridine treated dropwise with 28.6 g. of phosphorous tribromide in 120 ml. of hexane. The mixture is stirred for 20 minutes at 0° C., then poured onto ice water and extracted with ether. The ether extract is washed successively with water, a saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated. There is obtained 8-bromo-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl ester, which is processed as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Cc1ccc(Cn2ccc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-(4-methylbenzyl)-1H-indole (Step 1 of Example 25) and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 382. 1HNMR (300 MHz, DMSO-d6): δ 7.83 (s, 1H), 7.76 (d, 2H, J=8.8 Hz), 7.52 (s, 1H), 7.53 (d, 2H, J=8.1 Hz), 7.41-7.38 (m, 3H), 7.11 (m, 4H), 6.54 (d, 1H, J=3 Hz), 5.39 (s, 2H), and 2.23 ppm (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:10])[NH:8][CH3:9])=[C:5]([NH:11][C:12]([C:14]2[C:19](Br)=[CH:18][N:17]=[C:16]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[N:15]=2)=[O:13])[CH:4]=[N:3]1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[N:30][CH:31]=1>>[CH3:1][N:2]1[C:6]([C:7](=[O:10])[NH:8][CH3:9])=[C:5]([NH:11][C:12]([C:14]2[C:19]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:18][N:17]=[C:16]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[N:15]=2)=[O:13])[CH:4]=[N:3]1
Reactant: CNC(=O)c1c(NC(=O)c2nc(C3CCC3)ncc2Br)cnn1C
Reactant: Nc1cncnc1
Product: CNC(=O)c1c(NC(=O)c2nc(C3CCC3)ncc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 5-bromo-2-cyclobutyl-pyrimidine-4-carboxylic acid (1-methyl-5-methylcarbamoyl-1H-pyrazol-4-yl)-amide (23 mg, 58 μmol) and 5-aminopyrimidine (8 mg, 82 μmol) according to the method described in example A-1, step 2 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (1 mg, 5%).
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]>C1COCC1.C(O)C.[C].[Rh]>[CH3:1][CH:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1)[CH2:3][CH3:4]
Reactant: CCC(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: [Rh]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(C)c1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 86.9 %

Procedure:
A mixture of 5% rhodium-carbon (50% wet, 15 mg) and 9-[4-(1-methylpropyl)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF (30 mL) and ethanol (30 mL) was stirred under a hydrogen atmosphere (3 atm) at room temperature for 7 hr. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (132 mg) as a brown solid. The obtained solid was crystallized from THF and diisopropyl ether to give a brown solid.
Reaction SMILES: [F-].[K+].[Cl:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7](B2OCC(C)(C)CO2)=[CH:6][CH:5]=1.O.O.O.O.P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.[Na+].[Na+].[Na+].[NH2:59][C:60]1[C:65]([F:66])=[C:64](Cl)[N:63]=[C:62]([C:68]([O:70][CH3:71])=[O:69])[C:61]=1[Cl:72]>C(O[Pd]OC(=O)C)(=O)C.O.C(OCC)(=O)C.C(#N)C>[NH2:59][C:60]1[C:65]([F:66])=[C:64]([C:7]2[C:8]3[CH:9]=[CH:10][O:11][C:12]=3[C:4]([Cl:3])=[CH:5][CH:6]=2)[N:63]=[C:62]([C:68]([O:70][CH3:71])=[O:69])[C:61]=1[Cl:72]
Reactant: CC1(C)COB(c2ccc(Cl)c3occc23)OC1
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c3occc23)c(F)c(N)c1Cl
Yield: 17.1 %

Procedure:
Combined potassium fluoride (0.365 g, 6.28 mmol), diacetoxypalladium (0.047 g, 0.209 mmol), and 2-(7-chlorobenzofuran-4-yl)-5,5-dimethyl-1,3,2-dioxaborinane (0.609 g, 2.301 mmol), sodium 3,3′,3″-phosphinetriyltribenzenesulfonate tetrahydrate (0.134 g, 0.209 mmol), methyl 4-amino-3,6-dichloro-5-fluoropicolinate (0.5 g, 2.092 mmol). Added water (3 mL) and acetonitrile (1 mL). Heated reaction mixture at 150° C. in a microwave reactor for 6 minutes. Diluted cooled reaction mixture with ethyl acetate and water and filtered through cotton plug. Dried organic phase (Na2SO4) and concentrated under vacuum. Purified by reverse phase chromatography to provide the title compound as a white solid (127 mg, 12.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][NH:15][C@H:14](/[CH:17]=[CH:18]\[C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:15]2[CH2:16][C@H:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[CH2:13][C@H:14]2/[CH:17]=[CH:18]\[C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(/C=C\[C@@H]2C[C@@H](NS(=O)(=O)c3ccc(Cl)cc3)CN2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(/C=C\[C@@H]2C[C@@H](NS(=O)(=O)c3ccc(Cl)cc3)CN2S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a suspension of (2S,4R)-4-(4-chlorophenyl-sulfonylamino)-2-[(Z)-2-(4-methoxycarbonylphenyl)vinyl]pyrrolidine (11.5 g) in dichloromethane (200 ml) were added triethylamine (3.80 ml) and 4-chlorobenzenesulfonyl chloride (5.77 g) under ice bath cooling and the mixture was stirred at room temperature for 1 hour. The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residual solid was collected by filtration to give (2S,4R)-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-2-(4-methoxycarbonylphenyl)vinyl]pyrrolidine (15.71 g) as a white powder
Reaction SMILES: S(=[N:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[CH2:27][CH3:28])=[O:8])=O.Cl>ClCCl.O1CCCC1>[NH2:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:23])([F:24])[F:25])[C:18]([F:19])([F:20])[F:21])=[CH:12][C:11]=1[CH2:27][CH3:28])=[O:8]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N=S=O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-sulfinylamino-N-[2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.111 g, 0.237 mmol) (for example, Example 2.1) in dichloromethane (2 ml) and tetrahydrofuran (2 ml) was treated with aqueous hydrochloric acid (2N) (1 ml) and stirred at 25° C. for 30 minutes. The organic solvents were removed from the reaction mixture under reduced pressure. The residue was neutralized with aqueous sodium hydrogen carbonate (saturated) and was extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to yield the desired compound. 1H-NMR (CDCl3, 400 MHz): 7.44 (s, 1H), 7.38 (s, 2H), 7.30-7.20 (m, 3H), 6.89 (d, 1H), 3.85 (bs, 2H), 2.69 (q, 2H), 2.32 (s, 3H), 1.22 (t, 3H) ppm.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=2)=[O:16])[N:13]=1.[Cl-].[Be+2].[Cl-].CC[O:36]C(C)=O>C1(C)C=CC=CC=1>[OH:36][C:6]1[CH:5]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)=[O:16])[N:13]=2)[CH:3]=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COc1ccccc1-c1nc(NC(=O)Nc2cccc(CN3CCCCC3)n2)cs1
Agent: [Be+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(CN2CCCCC2)n1)Nc1csc(-c2cccc(O)c2)n1

Procedure:
A mixture of 1-[2-(3-methoxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea (Example 218) and beryllium chloride (5.0 eq) in dry toluene (0.2 M) and 4A molecular sieves was heated at reflux for 10 h. The starting material was not totally soluble in toluene. The mixture was brought to RT, diluted with EtOAc and washed with saturated NH4Cl. The organic phase was separated, dried over MgSO4, filtered, concentrated by rotary evaporation and purified by prep HPLC (Column Phenomenex type Prodigy 50 ODS3 100A size 250×21.20 mm 5u, Gradient 10% to 90% CH3CN:H2O containing 1% TFA over 20 min, Detector 254 nm, 4 nm Band) to afford the title compound as an off white solid. EI-MS m/z 410 (M+H). Calc'd for C21H23N5O2S: 409.16.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH:26]3[CH2:28][CH2:27]3)[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[C:29](Cl)(=[O:31])[CH3:30].O>N1C=CC=CC=1>[C:21]([O:20][C:19](=[O:25])[NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:29](=[O:31])[CH3:30])[S:3][C:4]=3[N:5]=2)[CH:26]2[CH2:28][CH2:27]2)[CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(N(c2ncc3nc(N)sc3n2)C2CC2)c1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(c3cccc(NC(=O)OC(C)(C)C)c3)C3CC3)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(cyclopropyl)amino]phenyl}carbamate (1.20 g, 3.01 mmol) in pyridine (20 mL) was added acetyl chloride (859 μL, 12.1 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water (60 mL), and the mixture was extracted with ethyl acetate (60 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and filtered through a basic silica gel pad. The filtrate was concentrated under reduced pressure to give tert-butyl(3-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl](cyclopropyl)amino}phenyl)carbamate as a dark-purple solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([F:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C.[NH3:20]>CO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]([C:4](=[O:3])[NH2:20])([F:19])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: N
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(F)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Fluoro-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.8 mmol, 0.5 g) was taken in 7M NH3 in MeOH (5 mL) and stirred at room temperature for 12 h in a sealed vial. All volatiles were removed under reduced pressure to provide 4-carbamoyl-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester as white solid.
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[F:19]>C(O)(C)C>[ClH:12].[F:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Fc1cnccc1Cl
Reactant: Nn1ccc2ccccc21
Agent: Cl
Solvent: CC(C)O
Product: Fc1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 4-chloro-3-fluoropyridine hydrochloride in isopropanol at 90° C. for 4 hours in substantially the same manner as in Example 17, m.p. >250° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=1)=[O:11]
Reactant: Cc1ccc(-c2ccc(C)cc2C(=O)O)nc1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccc(C)cc2C(=O)N2CCC[C@@H](C)[C@H]2CN)nc1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, starting with 5-methyl-2-(5-methylpyridin-2-yl)benzoic acid. ESI-MS (m/z): 338 [M+1]+.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14]>Cl.CN1C(=O)CCC1>[CH2:13]([O:15][CH:16]([O:12][CH2:1][CH:2]([O:3][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:4]([O:5][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:6]([O:7][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:8]([O:9][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH2:10][O:11][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH3:17])[CH3:14]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=COCC
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCOC(C)OCC(OC(C)OCC)C(OC(C)OCC)C(OC(C)OCC)C(COC(C)OCC)OC(C)OCC
Reaction time: 4.5 h

Procedure:
Into a 250 ml. flask, equi ped with static nitrogen head and magnetic stirrer, was charged 18.6 g. of mannitol, 100 ml. of N-methyl pyrrolidinone and 64.8 g. of ethyl vinyl ether. There was then added 10 drops of concentrated HCl and the mixture stirred at between 22° and 28° for 4.5 hours and allowed to stand overnight. The next day an infrared spectrum of an appropriately worked up sample showed the virtual absence of hydroxyl absorption and strong ether C--O--C bands. The reaction mixture was poured, with stirring, into 750 ml. of water containing excess NaOH and extracted twice with 150 ml. portions of hexane. Each extract was washed consecutively with two 750 ml. portions of water. The compbined oganic phases were dried over solid sodium carbonate-sodium sulfate and vacuum evaporated at about 10 mm. Hg to give 59 g. of crude oil. Distillation was performed on a short path micro still under the following conditions:
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10].[Cl:14][C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]3[N:44]=[C:30]4[CH:31]([C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=5)[CH2:32][C:33](=C)[CH2:34][CH2:35][N:29]4[N:28]=3)=[CH:22][C:21]=2[O:45][CH3:46])[CH:19]=1>O.C1COCC1.[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10].[Cl:14][C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]3[N:44]=[C:30]4[CH:31]([C:37]5[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=5)[CH2:32][C:33](=[O:2])[CH2:34][CH2:35][N:29]4[N:28]=3)=[CH:22][C:21]=2[O:45][CH3:46])[CH:19]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2C(c2ccc(F)cc2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of sodium periodate (138 mg, 0.645 mmol) in water (5.0 mL) was added over a 10 min period, via pipet, to a vigorously stirred solution of the N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (100 mg, 0.215 mmol, from example 133) and osmium tetroxide (5.47 mg, 0.022 mmol) in THF (5.0 mL). The reaction was stirred for 1 h and then diluted with water (150 mL)/brine (100 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound as the TFA salt (60 mg, 47% yield). LC-MS (M+H)+ 467.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.24 (1 H, br. s.), 8.12 (1 H, d, J=1.5 Hz), 7.33 (1 H, d, J=2.1 Hz), 7.19-7.24 (1 H, m), 7.07-7.18 (5 H, m), 4.71 (1H, dd, J=8.5, 4.0 Hz), 4.54-4.64 (1 H, m), 4.45-4.54 (1 H, m), 3.90 (3 H, s), 3.44 (1 H, dd, J=14.3, 8.5 Hz), 3.16 (1 H, dd, J=14.3, 4.0 Hz), 2.89-3.06 (2 H, m).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[C:26]([O:39][CH3:40])[C:27]([O:31][CH2:32][C:33]7[CH:38]=CC=C[CH:34]=7)=[CH:28][CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:41]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1.C(Br)C(C)C>>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[C:26]([O:39][CH3:40])[C:27]([O:31][CH2:32][CH:33]([CH3:38])[CH3:34])=[CH:28][CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:41]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: COc1c(OCc2ccccc2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12
Solvent: CC(C)CBr
Product: COc1c(OCC(C)C)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12

Procedure:
Synthesized according to the method of example 10 using 7-(2-methyl-1H-benzimidazol-6-yl)-4-{8-(methyloxy)-7-[(phenylmethyl)oxy]quinazolin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) in step 1 and isobutyl bromide in step 2. 1H NMR (400 MHz, d6-DMSO): 8.48 (s, 1H), 7.96 (s, 1H), 7.83 (m, 3H), 7.63 (d, 1H), 7.52 (d, 1H), 7.04 (d, 1H), 5.46 (s, 2H), 4.65 (br s, 3H) 4.53 (br s, 2H), 4.07 (d, 2H), 3.92 (s, 3H), 2.79 (s, 3H), 2.13 (m, 1H), 1.04 (d, 6H); MS (EI) for C30H31N5O3: 510 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.Cl.[F:24][C:25]1([F:29])[CH2:28][NH:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([CH3:21])([CH3:22])[CH2:19][N:27]3[CH2:28][C:25]([F:29])([F:24])[CH2:26]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: FC1(F)CNC1
Reactant: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)C=O)cn2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Product: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)CN3CC(F)(F)C3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yloxy)-2-methylpropanal (665 mg, 2.06 mmol, Eq: 1.00) in DCE (70 ml) was added 3,3-difluoroazetidine hydrochloride (347 mg, 2.68 mmol, Eq: 1.30). The mixture was stirred at RT for 1 h, then sodium triacetoxyborohydride (655 mg, 3.09 mmol, Eq: 1.5) was added and stirring was continued for 18 h. The reaction mixture was diluted with saturated NaHCO3 solution and extracted with DCM (5×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2-50 g, Hex:AcOEt, 7:3 in 20 min, then 50% in 30 min) to afford the desired product (566 mg) as a white powder. (M+H)+=400 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 2.79 (br. s., 2 H) 3.70-3.81 (m, 4 H) 3.83 (s, 3 H) 6.87 (dd, J=8.84, 0.51 Hz, 1 H) 7.32 (d, J=8.59 Hz, 1 H) 8.10 (d, J=2.78 Hz, 1 H) 8.22 (s, 1 H) 8.28 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:17][CH2:16][C:15]4[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=4[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[C:22](=[N:28][Si](C)(C)C)=[N:23][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]1)/[C:8]/2=[N:28]/[C:22]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1c2cc(Br)ccc2CC12CCc1ccccc1CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\c2cc(Br)ccc2CC12CCc1ccccc1CC2
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of 6′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-inden]-1′(3′H)-one (20 mg, 0.059 mmol) in DCM (2 mL) was added TiCl4 (44.7 mg, 0.235 mmol) dropwise, the mixture was stirred at 50° C. at Ar2 under microwave for 20 minutes, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (43.8 mg, 0.235 mmol) was added dropwise. The mixture was stirred at 60° C. at Ar2 under microwave for 10 minutes and repeated the same operation for one time and then poured into ice-water (10 mL). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude (Z)—N-(5′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-indene]-3′(1′H)-ylidene)cyanamide (20 mg, 4%).