Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12]([C:31]#[N:32])=[N:13][C:14]4[C:19]([C:20]=3[C:21]#[N:22])=[CH:18][C:17]([C:23]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)=[O:24])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([Mg]Br)=[CH:38][CH:37]=1.[CH2:44]1COCC1>C(OCC)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([C:31]#[N:32])=[N:13][C:14]4[C:19]([C:20]=3[C:21]#[N:22])=[CH:18][C:17]([C:23]([C:39]3[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=3)([OH:24])[C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)=[CH:16][C:15]=4[CH3:44])=[CH:33][CH:34]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C1CCOC1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: Cn1cncc1C(=O)c1ccc2nc(C#N)c(Cc3ccc(-n4cccn4)cc3)c(C#N)c2c1
Solvent: CCOCC
Product: Cc1cc(C(O)(c2ccc(Cl)cc2)c2cncn2C)cc2c(C#N)c(Cc3ccc(-n4cccn4)cc3)c(C#N)nc12
Reaction time: 0.25 h

Procedure:
A solution of LaCl3-2LiCl in THF (0.36 mL, 0.22 mmol, 0.6 M in THF) was added to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-(1-methyl-1H-imidazole-5-carbonyl)quinoline-2,4-dicarbonitrile (50 mg, 0.08 mmol, Intermediate 14: step e) in THF (1.8 mL) at room temperature. After 15 minutes of stirring, a solution of 4-chlorophenyl magnesium bromide (0.32 mL, 0.32 mmol) in diethylether was added dropwise at 0° C. After stirring for 30 minutes, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl and the mixture was partitioned between water and DCM. The layers were separated and the aqueous phase was further extracted with DCM. The organic layers were combined, washed with saturated aqueous NaCl solution, dried (MgSO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-7% MeOH-DCM) to provide the title compound. MS m/e 570.3 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.[N+](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N-]>C(Cl)Cl.CCOC(C)=O.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:1][CH:2]1[CH2:3][CH:4]2[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:8]([CH2:7][O:6][CH2:5]2)[CH2:9]1)[CH3:28]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1C2COCC1CC(O)C2
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)COC1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of benzyl 7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate O (200 mg, 0.72 mmol) in DCM (4 mL) was added ethyl 2-diazoacetate (202 mg, 1.44 mmol) and Rhodium(II) acetate (319 mg, 0.72 mmol) at 0° C. The resulting mixture was stirred at room temperature for overnight, and then diluted with EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine and dried (Na2SO4). The organic solvent was removed in vacuo to give the crude product, which was purified by column chromatography to give the intermediate benzyl 7-(2-ethoxy-2-oxo-ethoxy)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (144 mg, 55%). LC/MS: calc'd 364 (MH+), exp 364 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[CH2:33]([O:32][CH2:31][C@@:13]12[CH2:12][N:11]([S:8]([C:5]3[CH:6]=[N:7][C:2]([NH:36][CH3:35])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:20][CH2:19][C:18]1=[CH:17][C:16]1[N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:22]=[CH:23][C:15]=1[CH2:14]2)[CH3:34]
Reactant: CN
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(NC)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-4a-ethoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and methylamine. LCMS (Method B): 498 (M+H)+, Retention time 3.6 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:26]3[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: CC1CCNCC1
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(N3CCC(C)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 80 °C
Reaction time: 19.5 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol) in DMF (3.0 mL) was added 4-methylpiperidine (0.035 g, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 80° C. and stirring continued for 19.5 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-(4-methylpiperidin-1-yl)-pyridin-3-yl)quinoline as a tan solid. Mass Spectrum (ESI) m/e=388.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1([C:20]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:20]([N:15]4[CH2:16][CH2:17][CH2:18][CH2:19]4)=[O:21])[CH2:28][CH2:27]3)=[O:14])[CH2:9][S:8]2)[CH:2]=1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(=O)C2CSC(c3cccnc3)N2)CC1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a solution of 2-(3-pyridyl)thiazolidine-4-caroxylic acid 2.1 g, 1-(pyrrolidinecarbonylmethyl)piperazine 1.8 g, 1-hydroxybenzotriazole 1.5 g and N,N-dimethylformamide 50 ml was added dicyclohexylcarbodiimide 2 g under ice-cooling, and the mixture was stirred overnight at room temperature. The resultant dicyclohexylurea was filtered off and the filtrate concentrated under reduced pressure. To the residue were added ethyl acetate 100 ml and water 10 ml, the mixture was basified by addition of sodium carbonate, sodium chloride added until saturation and allowed to stand. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture solution of ethyl acetate - methanol (6:4) to give 2.1 g of 1-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]-4-[1-(pyrrolidinyl)carbonylmethyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]2[S:37][C:36]([C:38]3([O:42]CC4C=CC(OC)=CC=4)[CH2:41][O:40][CH2:39]3)=[N:35][CH:34]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:15]=3)[N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:33]2[S:37][C:36]([C:38]3([OH:42])[CH2:41][O:40][CH2:39]3)=[N:35][CH:34]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:15]=3)[N:8]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(-c4cnn(CCN6CCCC6)c4)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(CCN4CCCC4)c3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Reaction time: 0.5 h

Procedure:
To an ambient solution of 5-(5-chloro-2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(3-(4-methoxybenzyloxy)oxetan-3-yl)thiazole (Example 20B) (160 mg, 0.215 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (2.5 mL, 32.4 mmol). The reaction was stirred for 0.5 hours and then concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (5 mL) and saturated aqueous bicarbonate solution (1 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 0 to 10% methanol in dichloromethane, to give the title compound. MS ESI(+) m/z 625.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.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.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][CH2:55][C@H:54]([NH2:58])[CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>O>[NH2:1][C:2]1[C:3]([C:9]([NH:58][C@H:54]2[CH2:55][CH2:56][CH2:57][N:52]([C:50]([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:51])[CH2:53]2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2nc(Br)cnc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
3-amino-6-bromopyrazine-2-carboxylic acid (3.63 g, 16.65 mmol), HATU (9.49 g, 25.0 mg) and DIEA (4.35 mL, 25.0 mmol) was added to a solution of (s)-3-amino-piperidine-1-carboxylic acid tert-butyl ester (4.00 g, 19.97 mmol, commercially available from Astatech or Arch Corporation). It was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and extracted with ethyl acetate (2×150 mL) then dried over anhydrous sodium sulfate and filteration, concentration and purified by column chromatography to give 1,1-dimethylethyl (3S)-3-{[(3-amino-6-bromopyrazin-2-yl)carbonyl]amino}piperidine-1-carboxylate 5.00 g (75.0% yield): MS (EI) for C15H22BrN5O3: 401.12 (MH+).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromohexane (0.192 g, 1.16 mmol) in DMF (5.3 mL). Heat at 70° C. overnight, then increase the temperature to 100° C. for additional two hours. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine (1×50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 7% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2334, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.6 min, 97.8% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[C:34]([Cl:38])[C:35]=1[CH:36]=O)[O:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29]>>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[NH:7][C:5]([C:4]1[CH:18]=[CH:19][C:20]2[N:21]=[C:36]([C:35]3[C:34]([Cl:38])=[CH:33][C:25]([O:26][CH2:27][C:28](=[O:29])[N:30]([CH3:31])[CH3:32])=[CH:24][C:23]=3[Cl:22])[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: CN(C)C(=O)COc1cc(Cl)c(C=O)c(Cl)c1
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Product: CN(C)C(=O)COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide (from Example 6-17) and 2-(3,5-dichloro-4-formylphenoxy)-N,N-dimethyl-acetamide analogous to Example 6-17. 1H NMR (Methanol-d4, 400 MHz): δ 8.83 (d, 1H), 8.56 (d, 1H), 8.20 (t, 1H), 8.18 (t, 1H), 8.14 (d, 1H), 8.02 (m, 2H), 7.90 (d, 1H), 7.79 (t, 1H), 7.28 (s, 2H), 5.02 (s, 2H), 3.09 (s, 3H), 3.01 (s, 3H). MS (m/z) 534.2 (M+1); Retention time: 1.28 min (Method 10).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=3[O:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH2:7][CH2:6]2)[CH2:2]1.[Br:28][C:29]1[N:30]=[C:31](Br)[C:32]2[N:33]([CH:35]=[CH:36][N:37]=2)[CH:34]=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CC(O)C.C(Cl)Cl>[Br:28][C:29]1[N:30]=[C:31]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH:3]4[CH2:2][O:1][CH2:4]4)[CH2:6][CH2:7]3)=[C:12]([O:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:13]=2)[C:32]2[N:33]([CH:35]=[CH:36][N:37]=2)[CH:34]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: Nc1ccc(N2CCN(C3COC3)CC2)c(OCCOC2CCCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: ClCCl
Product: Brc1cn2ccnc2c(Nc2ccc(N3CCN(C4COC4)CC3)c(OCCOC3CCCCO3)c2)n1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)aniline XXIV (619 mg, 2.17 mmol) and 6,8-dibromoimidazo[1,2-a]pyrazine (601 mg, 2.2 mmol) in IPA (15 mL) was added N,N-Diisopropylethylamine (0.95 ml, 5.43 mmol). The mixture was stirred at 110° C. for 16 h. After this time, DCM (10 mL) and sat aqueous NaHCO3 (15 mL) were added. The aqueous layer was separated and extracted with DCM (2×10 mL). The combined organic extracts were washed with brine (10 mL) and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (24 g column) eluting with a gradient of 100% DCM—60:35:5 DCM:Et2O:MeOH to provide 6-bromo-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)imidazo[1,2-a]pyrazin-8-amine XXV.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[BH4-].[Na+].Cl>COCCOC.O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(Oc2cccc(C=O)c2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1cccc(Oc2cccc(CO)c2)c1
Reaction time: 4 h
Yield: 82.6 %

Procedure:
3-(3-Methylphenoxy)benzaldehyde (5.80 g, 27.3 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (30 mL) and tetrahydrofuran (30 mL), sodium borohydride (0.567 g, 15.0 mmol) was added under ice-cooling and the mixture was stirred at the same temperature for 4 hrs. Dil. hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (4.83 g, yield 83%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11]([N:16]2[CH2:21][CH:20]=[C:19]([C:22](O)=[O:23])[CH2:18][CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:9][C:10]1[C:11]([N:16]2[CH2:17][CH:18]=[C:19]([C:22]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:23])[CH2:20][CH2:21]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)C1=CCN(c2ncccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloroaniline (13.2 g, 103 mmol), 3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid (16.49 g, 69.1 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (26.5 g, 138 mmol) were combined in dichloromethane (150 mL) and stirred overnight at ambient temperature. The mixture was diluted with dichloromethane (200 mL), washed with water (400 mL), 400 mL brine, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexane:ethyl acetate (7:3) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.20 (dd, 1H), 7.70 (dd, 1H), 7.62 (s(br) 1H), 7.54 (d, 2H), 7.30 (d, 2H), 6.92 (dd, 1H), 6.76 (m, 1H), 4.16 (dd, 2H), 3.64 (dd, 2H), 2.66 (m, 2H); MS (ESI) 349 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[Cl-].[Cl-].[Cl-].[Al+3].[C@@H:15]12[C:24](=[O:25])[O:23][C:21](=[O:22])[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[C:24]([C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([OH:23])=[O:22])=[O:25]
Reactant: COc1ccccc1OC
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)[C@H]2CCCC[C@H]2C(=O)O)cc1OC

Procedure:
0.5 mole of 1,2-dimethoxybenzene was added slowly to a suspension of 0.5 mole aluminiumtrichloride in 1 l of dichloromethane at 0° C. After complete addition, cis-cyclohexane-1,2-dicarboxylic anhydride was added to the solution. After 8 hours of reflux the solution was poured onto ice. The organic layer was dried over magnesium sulfate and evaporated. The residue was washed with diethyl ether and dried. M.p. 171°-175° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46]([O:48][CH2:49][C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[O:47])=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C.Cl.[CH3:57][O:58][C:59]([NH:61][CH:62]([CH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1)[C:63]([OH:65])=O)=[O:60].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>C(Cl)Cl.CO>[CH2:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[C:38]1[NH:37][C:36]([C:31]2[CH:30]=[CH:29][C:28]3[C:33](=[CH:34][CH:35]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([C:17]5[NH:16][C:15]([CH:9]6[CH2:10][C:11]([F:14])([F:13])[CH2:12][N:8]6[C:63](=[O:65])[CH:62]([NH:61][C:59]([O:58][CH3:57])=[O:60])[CH:66]6[CH2:71][CH2:70][O:69][CH2:68][CH2:67]6)=[N:19][CH:18]=5)=[CH:21][CH:22]=4)[CH:27]=3)[CH:32]=2)=[CH:40][N:39]=1)=[O:47])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc4c3)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc4c3)cc2)[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 45.3 %

Procedure:
To a solution of 2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.34 mmol) in CH2Cl2 (3.5 mL) and MeOH (0.25 mL) was added HCl (in dioxanes, 4 M, 1.7 mL, 7.8 mmol). The solution was stirred at room temperature for 2.5 h and concentrated to dryness. The resulting solid was slurried in CH2Cl2 (3 mL) and DMF (1 mL). Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.11 g, 0.50 mmol), HATU (0.15 g, 0.40 mmol), and DIPEA (0.3 mL, 1.7 mmol) were added. The resulting solution was stirred at room temperature for 18 h. The solution was diluted with CH2Cl2 and washed with saturated sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 2→20% MeOH in CH2Cl2), followed by preparative HPLC (Gemini, 15→50% MeCN in H2O (0.1% TFA)) to provide 2-(5-{6-[4-(2-{4,4-Difluoro-1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester (0.13 g, 46%). LCMS-ESI+: calc'd for C47H47F2N7O6: 843.36 (M+); Found: 844.78 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:31]([Cu])#[N:32].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:31]#[N:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Temperature: 120 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of 1-bromo-4-hydroxy-6-(4-propoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (315 mg, 0.664 mmol), CuCN (66 mg, 0.730 mmol), and N-methylpyrrolidinone (2 mL) was stirred at 120° C. for 4 h. After cooling to room temperature the mixture was poured into EtOAc (20 mL) and saturated ammonium hydroxide solution (˜1 mL) was added. The mixture was rapidly stirred for 2 min. Then it was acidified with concentrated HCl, washed with water, and saturated NaCl solution before it was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography to give title compound (206 mg). ESI MS (m/z): 421 (M+H+).
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O.[C:13]([OH:17])(=O)[CH:14]=O.O.[NH2:19][NH2:20]>>[N:19]1[NH:20][C:13](=[O:17])[CH:14]=[C:2]2[C:1]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][CH2:3]2
Reactant: NN
Reactant: O=CC(=O)O
Reactant: O=C1CCCc2ccccc21
Solvent: O
Product: O=c1cc2c(n[nH]1)-c1ccccc1CC2

Procedure:
In a manner similar to that described in Preparation 3, 1-tetralone was treated with glyoxylic acid monohydrate and hydrazine hydrate to give 5,6-dihydrobenzo[h]cinnolin- 3[2H]-one (m.p. 260-1°; from ethanol) ν(Nujol mull) 3350-2200, 1665, 1610 and 1600 cm-1 ; δ(DMSO-d6) 2.88 (4H,s,5,6-H2), 6.77 (1H,s,4-H), approx 7.3 (3H,m,7,8,9-H), 7.92 (1H,m,10-H), 12.9 (1H,br,NH).