Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CO[C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13](COC)=[N:12][C:11]=1[NH2:19].N.[O:22]1[CH2:26]CC[CH2:23]1>>[NH2:19][C:11]1[C:10]([CH2:9][OH:20])=[C:15]([CH2:23][O:22][CH3:26])[CH:14]=[CH:13][N:12]=1
Reactant: C1CCOC1
Reactant: COCc1ccc(C(=O)OC)c(N)n1
Agent: N
Agent: [Al+3]
Agent: [H-]
Product: COCc1ccnc(N)c1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a mixture of lithium aluminum hydride (80%, 220 mg, 4.6 mmol) and tetrahydrofuran (5 mL) was added 2-amino-6-methoxymethyl-nicotinic acid methyl ester (300 mg, 1.5 mmol) described in Manufacturing Example 26-1-4 at 0° C., which was stirred for 20 minutes at the same temperature. An aqueous 28% ammonia solution was added dropwise to the reaction mixture at 0° C. The mixture was warmed to room temperature and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (260 mg, 100%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.C(Cl)Cl.[C:17]1([C:23](=[N:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:17]1([C:23](=[N:30][CH:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=2)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(Cc1ccc(OC(F)(F)F)cc1)N=C(c1ccccc1)c1ccccc1
Reaction time: 1.5 h
Yield: 77.6 %

Procedure:
1-(Bromomethyl)-4-(trifluoromethoxy)benzene (1.23 mL, 7.7 mmol) and tetrabutylammonium hydrogen sulfate (2.85 g, 8.4 mmol) were added to a methylene chloride (50 mL) solution of tert-butyl [(diphenylmethylene)amino]acetate (compound described in J. Org. Chem., (1982), 47, 2663-2666, 2.07 g, 7.0 mmol) at room temperature according to the method described in the document (J. Org. Chem., (1995), 60, 601-607), and subsequently a 10% sodium hydroxide aqueous solution (21 mL) was added thereto. The mixture was vigorously stirred for 1.5 hours, and then to the reaction solution was added water. The resulting mixture was extracted with methylene chloride. The organic layer was collected, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (n-hexane to n-hexane:ethyl acetate, 19:1 and 9:1, V/V) twice to give 2.55 g of the title compound (white powder, yield: 78%).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:24]([Li])[CH2:25][CH2:26]C.C(Br)C=C>O1CCCC1>[CH2:1]([C:2]([CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:3])[CH2:26][CH:25]=[CH2:24]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
By reaction of 15.0 g of methylcarbonylmethylenetriphenyl phosphorane in 471 ml of tetrahydrofuran with 31.0 ml of butyllithium and 4.28 ml of allyl bromide analogously to 7, the title compound is obtained as crystallized oil with a melting point of 92°-93° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][N:6]2[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8]/[C:7]/2=[N:15]\[C:16](=[O:26])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])[CH2:2]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1.CCOC(C)=O>[C:11]([C:9]1[S:8]/[C:7](=[N:15]\[C:16](=[O:26])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])/[N:6]([CH2:5][CH:3]2[CH2:4][N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:2]2)[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1CNC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The TFA salt of Example 63C (0.25 g, 0.64 mmol) was dissolved in 3 mL of THF. The mixture was cooled to 0° C. and triethylamine (0.27 mL, 1.9 mmol) was added. Methanesulfonyl chloride (0.1 ml, 1.3 mMol) was added dropwise and the reaction was stirred at 0° C. for 30 minutes. The reaction was diluted with EtOAc, washed with water, brine, dried with MgSO4 and the solvent removed. Final product was purified by flash chromatography using a gradient from 0 to 100% EtOAc in hexane over 300 mL. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.35 (s, 9H) 2.85 (s, 3H) 3.16-3.30 (m, 1H) 3.84 (dd, J=8.14, 5.76 Hz, 2H) 3.90 (s, 3H) 4.04 (t, J=8.31 Hz, 2H) 4.42 (d, J=7.46 Hz, 2H) 6.63 (s, 1H) 6.92 (d, J=9.16 Hz, 1H) 7.34 (dd, J=8.82, 2.71 Hz, 1H) 7.91 (d, J=2.71 Hz, 1H). MS (DCI/NH3) m/z 472.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[CH:9]2.Br[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][CH3:30])=[N:21][CH:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH3:30][O:29][C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[CH:9]3)=[CH:20][N:21]=1
Reactant: Cn1c(=O)ccc2cc(OCCCN)ccc21
Reactant: COc1ncc(Br)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(NCCCOc2ccc3c(ccc(=O)n3C)c2)c2ccccc12
Temperature: 80 °C
Yield: 25.5 %

Procedure:
6-(3-Amino-propoxy)-1-methyl-1H-quinolin-2-one(232 mg), 4-bromo-1-methoxy-isoquinoline(286 mg), palladium acetate (II) (22 mg), xantphos (558 mg), and sodium t-butoxide(192 mg) were added to dioxane(10 ml). The mixture was heated at 80° C. for overnight under argon atmosphere. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, and followed by celite filtration. The filtrate was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane=2:1→1:0). The purified product was condensed under reduced pressure to give the title compound(99 mg) as a brown amorphous solid.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[O:11])[CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][CH:23]=1.Cl>O1CCCC1.O>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]([CH:16]([CH3:17])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[O:11])[CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(-c2c(N)cc(C(=O)N(C(C)C)C(C)C)cc2[N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1cc(N)c(-c2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1)C(C)C
Yield: 84.5 %

Procedure:
0.64 ml of 2N sodium hydroxide were added to a solution of 235 mg of product A in 4 ml of tetrahydrofuran and the mixture was heated under refluxed for 2 hours. Then, the reaction mixture was diluted with 10 ml of water and the pH was adjusted to 9 with 1N hydrochloric acid. Washing was carried out with ethyl acetate and the pH is adjusted to 5 with 1N hydrochloric acid. Extraction was carried out with ether and the ethereal phases were dried with MgSO4, followed by evaporation under reduced pressure. The residue was crystallized from ether to obtain 191.7 mg of the expected product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]2[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([CH:17]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2]1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.[F:29][C:30]([F:47])([F:46])[C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37](N2C=CN=C2)=[O:38])=[CH:33][CH:32]=1.Cl>C(OCC)(=O)C.O>[F:29][C:30]([F:46])([F:47])[C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]3[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:17]=3)[CH2:2]2)=[O:38])=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cc([C@H]2CCCNC2)ccc1C
Reactant: O=C(OCc1ccc(C(F)(F)F)cc1)n1ccnc1
Agent: Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc([C@H]2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.8 %

Procedure:
(R)-Ethyl 5-(3-piperidinyl)-2-methylbenzoate-D-tartaric acid (2.02 g, 5.08 mmol) was dissolved in 100 mL ethyl acetate and washed with 100 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 10 mL toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (1.37 g, 5.08 mmol) was added. The reaction was stirred for 72 h at room temperature under nitrogen. The reaction was diluted with water (200 mL), acidified with 1N aqueous hydrochloric acid and extracted with diethyl ether (2×150 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 10% ethyl acetate/hexanes to yield 2.12 g (93%) of the desired (R)-3-(3-ethoxycarbonyl-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a clear oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C@@H:14]3[C@@H:17]([CH3:18])[C:16](=[O:19])[N:15]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:28]>C1COCC1>[NH2:28][C:16](=[O:19])[C@H:17]([CH3:18])[C@H:14]([NH:15][C:20](=[O:21])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:12]1[N:13]=[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][N:9]2[CH:11]=1
Reactant: [NH4+]
Reactant: C[C@H]1C(=O)N(C(=O)OC(C)(C)C)[C@@H]1c1cn2cc(C(C)(C)C)ccc2n1
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](C(N)=O)[C@H](NC(=O)OC(C)(C)C)c1cn2cc(C(C)(C)C)ccc2n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(2S,3R)-tert-butyl 2-(6-(tert-butyl)imidazo[1,2-a]pyridin-2-yl)-3-methyl-4-oxoazetidine-1-carboxylate (Preparation 38) was dissolved in THF (10 mL) and excess 28% aqueous ammonium hydroxide solution (ca 3 mL) added. The reaction was stirred in a sealed vial at 50° C. for 18 hours. The solvent was removed in vacuo to afford 311 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1.CC1C=CC(C(C)C)=CC=1>[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([OH:18])=[CH:13][CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=C1CCCc2cc(-c3ccc(O)cc3)ccc21
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: Oc1ccc(-c2ccc3c(O)cccc3c2)cc1
Yield: 51.9 %

Procedure:
To a 25 mL flask was added 6-(4-hydroxyphenyl)-1-tetralone (500 mg, 2.12 mmol), palladium on carbon (510 mg) and p-cymene (15 mL). The mixture was heated to reflux for 24 h, cooled, filtered through celite and extracted with 1 M NaOH (2×25 mL). The aqueous layer was then acidified, extracted with ether (3×), and passed through a silica plug. Concentration under reduced pressure afforded 260 mg (53%) product as a brown solid: mp above 200° C. (dec.); 1H NMR (300 MHz,-DMSO-d6) δ 6.82. (1H, d, J=7.5 Hz), 6.87 (2H, d J=8.1 Hz), 7.29 (1H, t, J=7.5 Hz), 7.38 (1H, d, J=7.5 Hz), 7.63 (2H, d, J=8.2 Hz), 7.70 (1H, d, J=8.5 Hz), 7.99 (1H, s) 8.14 (1H, d, J=8.5 Hz), 9.59 (1H, s), 10.09 (1H, s); MS m/z 235 (M−H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:15]2[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:17](=[O:34])[NH:16]2)=[C:7]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:35][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC.C(O)(=O)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:15]2[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)[C:17](=[O:34])[N:16]2[CH3:35])=[C:7]([S:9]([N:12]([CH3:13])[CH3:14])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(C)C)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}-N,N-dimethylbenzene sulfonamide (50 mg, 108 μmol) was initially charged in absolute THF (4.5 ml), and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (130 μl, 130 μmol; 1.2 eq.) was added at −78° C. After 30 min of stirring, iodomethane (77 mg, 542 μmol; 5 eq.) in THF (1 ml) was added, and the mixture was stirred for 16 h with gradual warming from −78° C. to RT. A little acetic acid was then added, and the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (7.6 mg, 14% of theory).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=[N:5]1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[F:28][C:2]([F:27])([F:1])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:29](=[O:31])[CH3:30])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=[N:5]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(CC(F)(F)F)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2OCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(2,2,2-trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 484, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: [N:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21]C3C=CC=CC=3)=[CH:16][CH:15]=2)=[N:12][C:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-].Cl[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1Cl>>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]2[C:13]3[N:12]=[C:11]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=3[NH:1][C:15]=2[CH:16]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OCc3ccccc3)cc2)c1N=[N+]=[N-]
Reactant: Clc1ccccc1Cl
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OCc3ccccc3)ccc12

Procedure:
A solution of methyl 3-azido-2-(4-(benzyloxy)phenyl)-6-(4-methoxyphenyl)isonicotinate (Example 205C, 356 mg, 0.763 mmol) in 1,2-dichlorobenzene (10 mL) was heated at 165° C. for 20 min. The solvent was removed under a stream of nitrogen to leave crude methyl 7-(benzyloxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate as a yellow solid: 1H NMR (CDCl3) δ ppm 9.37 (1H, s), 8.29 (1H, d, J=8.85 Hz), 8.13 (1H, s), 8.07-8.12 (2H, m), 7.47-7.51 (2H, m), 7.38-7.44 (2H, m), 7.31-7.37 (1H, m), 7.00-7.05 (3H, m), 5.19 (2H, s), 4.07 (3H, s), 3.88 (3H, s). This was suspended in a solution of 7 N ammonia in methanol (12 mL) and heated in a sealed microwave vial at 60° C. for 36 hr. The solvent was removed and the residue was dissolved in methylene chloride. An equal volume of hexane was added and the precipitate was collected by filtration. This gave 160 mg of 7-(benzyloxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide as a yellow solid. MS (ESI) m/z 424.1 (M+H). 1H NMR (DMSO-d6) δ ppm 11.38 (1H, s), 8.55 (1H, br. s.), 8.28 (1H, s), 8.23 (2H, d, J=8.85 Hz), 8.12 (1H, d, J=8.55 Hz), 7.83 (1H, br. s.), 7.49-7.57 (2H, m), 7.44 (2H, t, J=7.48 Hz), 7.31-7.40 (2H, m), 7.10 (2H, d, J=8.85 Hz), 6.97 (1H, dd, J=8.70, 2.29 Hz), 5.22 (2H, s), 3.85 (3H, s).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][C:26]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:36]5[CH:35]=[N:34][N:33]([C:26]([CH3:25])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1

Procedure:
9-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate were coupled under Suzuki conditions to give ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate. LC/MS (ESI+): m/z 490 (M+H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][N:52]1[CH:56]=[CH:55][CH:54]=[C:53]1[C:57]([NH:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:58]>CN(C)C=O.ClCCl>[F:15][C:14]([F:17])([F:16])[CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[NH:51][N:52]1[CH:56]=[CH:55][CH:54]=[C:53]1[C:57](=[O:58])[NH:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
421 mg (1.64 mmol) of 2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid were suspended in a mixture of N,N-dimethylformamide (5 mL) and dichloromethane (5 mL) and HATU (624 mg, 1.64 mmol) and DIEA (286 μl, 1.64 mmol) were added. The resulting suspension was stirred at room temperature for 2 hours and then 1-amino-N-phenyl-1H-pyrrole-2-carboxamide (300 mg, 1.49 mmol) was added. The resulting solution was stirred at room temperature overnight and the dichloromethane was removed in vacuum. 25 mL of water were added to the remaining solution and, after vigorous stirring, the solid that formed was filtered and washed with water. 582 mg (89% yield) of the title compound were obtained as a white solid.
Reaction SMILES: Br[C:2]1([F:10])[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6].NCCN>[Ni].C(O)C>[F:10][CH:2]1[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C1CC1(F)Br
Agent: [Ni]
Solvent: CCO
Solvent: NCCN
Product: CCOC(=O)C1CC1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
An internal glass tube was introduced into an autoclave and 0.5 g of ethyl 2-bromo-2-fluoro-1-cyclopropanecarboxylate (cis:trans=0.8:1), 0.5 ml of Raney nickel and 5 ml of ethanol were fed thereinto. Then 0.43 g of 1,2-diaminoethane was further added and the mixture was stirred at room temperature under a hydrogen gas atmosphere (1 kgf/cm2) for 24 hours. After the completion of the reaction, the catalyst was filtered off. Then the reaction mixture containing the title compound was analyzed by gas chromatography. As a result, it was found out that the reaction conversion rate was 100%, the yield was 78% and the cis:trans ratio was 0.8:1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Mg]Cl)(C)C.[CH2:27]([O:34][C:35](=[O:47])[NH:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH:44]=[O:45])[C:38]=1[F:46])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1[Mg]Cl>O1CCCC1>[CH2:27]([O:34][C:35](=[O:47])[NH:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH:44]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:9]=2)[OH:45])[C:38]=1[F:46])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ncnc32)cc1
Agent: CC(C)[Mg]Cl
Agent: Cc1ccccc1[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C(O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c3c(Cl)ncnc32)cc1
Temperature: -50 °C
Yield: 26.9 %

Procedure:
In a round bottom flask, 4-chloro-5-iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (29, 1.549 g, 3.572 mmol) is combined with 25.0 mL of tetrahydrofuran and the solution is cooled to −50° C. under nitrogen. Isopropylmagnesium chloride (2.76 mL, 2.0 M in tetrahydrofuran, 5.00 mmol) is added slowly and the reaction is allowed to warm to 5° C. over 70 minutes, then cooled to −45° C. In a separate vessel, (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (33, 805 mg, 2.76 mmol) in 5 mL of tetrhydrofuran is cooled to −5° C. and o-tolylmagnesium chloride (2.76 mL, 1 M in tetrahydrofuran, 2.76 mmol) is added dropwise slowly, maintaining the temperature at −5° C. for 1 hour. This is then cooled to −30° C. and added to the above 4-chloro-5-iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine reaction mixture. The resulting reaction mixture is warmed to room temperature over 2-3 hours, then quenched with the addition of 1 M aqueous citric acid and extracted with ethyl acetate. The organic layer is washed with water, brine and dried over magnesium sulfate, then filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (34, 445 mg). MS (ESI) [M+H+]+=598.8.