Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:33]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]>>[CH2:33]([N:37]1[CH2:42][CH2:41][N:40]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)s3)cc2)c1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)s4)cc3)c2)CC1
Yield: 58 %

Procedure:
The title compound was prepared from 5-((4-(3-(3-cyanophenyl)ureido) phenylsulfonamido)methyl)thiophene-2-sulfonamide following procedure C and using 2.2 equivalent of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1([CH3:23])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>ClCCl>[CH3:8][O:9][C:10]1([CH3:23])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: COC1(C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(C)CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
Trifluoroacetic acid (2.54 mL, 32.97 mmol) was added dropwise to tert-butyl 4-methoxy-4-methylpiperidine-1-carboxylate (22) (756 mg, 3.30 mmol) in dichloromethane (10 mL) at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 15 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford the desired compound as an oil (235 mg, 55.2%); 1H NMR (400.132 MHz, CDCl3) δ 1.15 (3H, s), 1.41-1.49 (2H, m), 1.68-1.74 (2H, m), 2.76 (2H, dt), 2.93 (2H, dt), 3.19 (3H, s), 3.49 (1H, s).
Reaction SMILES: CON(C)C([C:6]1[CH:14]=[C:13]2C(C(C)=C[N:12]2[CH2:15][C:16]2[CH:21]=CC(OC)=[CH:18][CH:17]=2)=CC=1)=O.C([Li])CCC.CN(C)C=[O:34].[Cl-].[NH4+]>C(OCC)C>[CH3:21][C:16]1[CH:15]=[N:12][CH:13]=[C:14]([CH3:6])[C:17]=1[CH:18]=[O:34]
Reactant: COc1ccc(Cn2cc(C)c3ccc(C(=O)N(C)OC)cc32)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cncc(C)c1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of 4-bromo-3,5-dimethylpyridine (3.72 g, Reference Example 25) in diethyl ether (50 ml), at −78° C. and under nitrogen, was treated dropwise with n-butyl lithium (0.025 ml, 1.6M). After stirring at −78° C. for 1 hour the resulting homogeneous solution was treated with dry dimethylformamide (6 ml) whilst maintaining the temperature below −65° C. The reaction mixture was allowed to warm to room temperature over 1 hour, then treated with a saturated aqueous solution of ammonium chloride (10 ml), and then extracted twice with ethyl acetate (100 ml). The combined extracts were evaporated to yield an orange oil which was subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate and pentane (1:4, v/v) to afford the title compound (2.3 g) as a semi-solid.
Reaction SMILES: [CH:1]1([N:4]2[C:12](=[O:13])[C:11]3[NH:10][C:9]([C:14]4[CH:15]=[N:16][C:17]([NH:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=4)=[N:8][C:7]=3[N:6]([CH2:25][CH2:26][CH3:27])[C:5]2=[O:28])[CH2:3][CH2:2]1.O1CCCC1.C(N(CC)C(C)C)(C)C.[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][N:45]=1>O>[CH:1]1([N:4]2[C:12](=[O:13])[C:11]3[NH:10][C:9]([C:14]4[CH:19]=[CH:18][C:17]([N:20]([CH2:21][CH2:22][O:23][CH3:24])[C:48](=[O:49])[C:47]5[CH:51]=[CH:52][C:44]([F:43])=[N:45][CH:46]=5)=[N:16][CH:15]=4)=[N:8][C:7]=3[N:6]([CH2:25][CH2:26][CH3:27])[C:5]2=[O:28])[CH2:2][CH2:3]1
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: CCCn1c(=O)n(C2CC2)c(=O)c2[nH]c(-c3ccc(NCCOC)nc3)nc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCn1c(=O)n(C2CC2)c(=O)c2[nH]c(-c3ccc(N(CCOC)C(=O)c4ccc(F)nc4)nc3)nc21
Temperature: 60 °C
Reaction time: 12 h

Procedure:
1-Cyclopropyl-8-[6-(2-methoxy-ethylamino)-pyridin-3-yl]-3-propyl-3,7-dihydro-purine-2,6-dione (2 g, 5.20 mmol) is charged to a reaction flask, followed by anhydrous tetrahydrofuran (25 ml) and N,N-diisopropylethylamine (5 eq). 6-fluoronicotinoyl chloride (1.16 g, 7.28 mmol, 1.4 eq) is added and the mixture is heated to 60° C. It is held for 12 hr and sampled for reaction completion via HPLC: When the reaction is complete, it is cooled to room temperature and water is added then filtered. The filtrate is concentrated then the resulting product is triturated with methanol at 60° C. then cooled to room temperature and filtered. The crude product was again triturated with methanol, filtered and again washed with methanol. The product is then dried at 50° C. to provide 2.41 g (91%). 1H NMR (400 MHz, DMSO-d6) δ 13.95 (1H), 8.9 (1H), 8.32 (1H), 8.15 (1H), 7.89 (1H), 7.39 (1H), 7.15 (1H), 4.2 (2H), 3.95 (2H), 3.6 (2H), 3.18 (3H), 2.6 (1H), 1.7 (2H), 1.05 (2H), 0.9 (3H), 0.7 (2H); m/z (ES+) 508.53
Reaction SMILES: [NH2:1][CH:2]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:7][CH:6]1[CH2:24][CH2:25][C:26]#[N:27])=[O:4].[C:36]([NH:39][C@H:40]([C:49](O)=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)(=[O:38])[CH3:37].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C.O>[C:36]([NH:39][CH:40]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=1)[C:49]([NH:1][CH:2]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:7][CH:6]1[CH2:24][CH2:25][C:26]#[N:27])=[O:4])=[O:50])(=[O:38])[CH3:37]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: N#CCCC1CN(CCc2ccc3ccccc3c2)C(=O)CN1C(=O)C(N)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NC(Cc1ccc(F)cc1)C(=O)N1CC(=O)N(CCc2ccc3ccccc3c2)CC1CCC#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[1-[2-amino-3-(4-fluorophenyl)proponyl]-4-(2-naphthalen-2-ylethyl)-5-oxo-piperazin-2-yl]propionitrile, 33, (47.2 g, 100 mmol), N-acetyl-L-tyrosine (22.3 g, 120 mmol), 1-hydroxybenzotriazole (16.2 g, 120 mmol), and N-methylmorpholine (132 mL, 120 mmol) in DMF (150 mL) is cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24.9 g, 130 mmol) is slowly added. The resulting mixture is stirred for 2 hours at 0° C. then allowed to warm and stir at room temperature another 2 hours. The reaction solution is diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc and extracted with water, dried and concentrated in vacuo to afford the crude product which is purified over silica gel.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(C(C)C)CC)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.CN(C)C=O>[NH2:8][C:7]1[C:2](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH3:46])=[O:43])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1cc(Cl)cnc1Cl
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ncc(Cl)cc1N

Procedure:
A N,N-dimethylformamide suspension (406 ml) of 2,5-dichloropyridine-3-amine (81.2 g), palladium acetate (11.2 g), 1,4-bis(diphenylphosphino)butane (42.5 g), ethyl acrylate (109 ml), diisopropylethylamine (174 ml) and tetrabutylammonium bromide (161 g) was stirred at 140° C. for 30 hours. After the reaction solution was brought back to room temperature, ethyl acetate and water were added and the solution was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added a 50% ethyl acetate-hexane mixed solvent, followed by stirring. The insolubles were filtered off, and washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl (2E)-3-(3-amino-5-chloropyridin-2-yl)acrylate (50.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[C@@H:10]([NH2:12])[CH3:11])=[CH:4][CH:3]=1.[OH:21][C:22]([CH3:32])([CH3:31])[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:19]#[N:20])[C@@H:10]([NH:12][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([OH:21])([CH3:32])[CH3:31])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(O)C(=O)c1ccccc1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H](NC(c1ccccc1)C(C)(C)O)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reaction time: 3 h

Procedure:
To a solution of 250 mg (0.877 mmol) of 3-(4-chlorophenyl)-2(S)(3-cyanophenyl)-1(S)-methyl-propylamine in 3 mL of dichloroethane, 134 μL (0.88 mmol) of 2-hydroxy-2-methylpropiophenone and 280 mg (1.32 mmol) of sodium triacetoxyborohydride were added. After stirring for 3 hr, the reaction was quenched with water and the organic layer was removed with a pipet. This layer was purified by prep TLC using 50% EtOAc/hexane as an eluant to isolate 3-(1(S)-(4-chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer A) as a higher Rf isomer (LC-MS: m/e=433 (M+1), 3.09 min) and 3-(1(S)-(4-Chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer B) as a lower Rf isomer. LC-MS: m/e=433 (M+1), 3.09 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[N:5]=2.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>N1C=CC=CC=1>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH3:19])=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.6 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-ethylphenyl}-3-(1-cyano-1-methylethyl)benzamide (270 mg, 0.59 mmol) in pyridine (6.0 mL) was added cyclopropanecarbonyl chloride (70 μL, 0.767 mmol), and the mixture was stirred at room temperature for 12 hr. Cyclopropanecarbonyl chloride (35 μL, 0.383 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (50 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (188 mg, 61%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[C:5](/[N:7]=[C:8]1/[N:9]([C@@H:30]2[CH2:35][CH2:34][C@H:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[N:13]=[CH:12][C:11]=2[NH:29]/1)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[F:55][C:56]1([F:60])[CH2:59][NH:58][CH2:57]1>CN(C=O)C.C(Cl)Cl>[F:55][C:56]1([F:60])[CH2:59][N:58]([C:36]([C@@H:33]2[CH2:34][CH2:35][C@H:30]([N:9]3[C:10]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]5[CH2:20][CH2:21][CH:22]([C:25]([OH:28])([CH3:26])[CH3:27])[CH2:23][CH2:24]5)[N:13]=[CH:12][C:11]=4[NH:29]/[C:8]/3=[N:7]\[C:5](=[O:6])[C:4]3[CH:39]=[CH:40][CH:41]=[C:2]([F:1])[CH:3]=3)[CH2:31][CH2:32]2)=[O:37])[CH2:57]1
Reactant: FC1(F)CNC1
Reactant: CC(C)(O)C1CCN(CCOc2cc3c(cn2)[nH]/c(=N\C(=O)c2cccc(F)c2)n3[C@H]2CC[C@@H](C(=O)O)CC2)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)C1CCN(CCOc2cc3c(cn2)[nH]/c(=N\C(=O)c2cccc(F)c2)n3[C@H]2CC[C@@H](C(=O)N3CC(F)(F)C3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of cis-4-((E)-2-(3-fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylic acid (0.05 g, 0.088 mmol) in DMF (1 mL) was added CDI (0.029 g, 0.176 mmol), and the resulting mixture was stirred at RT for 1 hour. To this mixture was added 3,3-difluoroazetidine hydrochloride (0.057 g, 0.440 mmol), and the mixture was stirred at RT for 1 hour. The mixture was diluted with DCM (10 mL) and washed with aqueous NH4Cl (5 mL) and brine (5 mL). The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (5-75% ACN/H2O; 0.1% TFA) to afford (E)-N-(1-(cis-4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-fluorobenzamide (35 mg, 61.8% yield). MS m/z=643.2 [M+H]. Calc'd for C33H41F3N6O4: 642.3.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)([CH2:13][OH:14])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.C(OCC)C>[CH2:1]([O:8][CH2:9][C:10]1([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[CH2:13][O:14][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CO)(COCc1ccccc1)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Brc1ccc(C2(COCc3ccccc3)COC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a solution of 2-Benzyloxymethyl-2-(4-bromo-phenyl)-propane-1,3-diol (475 mg, 1.35 mmol) in THF (5 mL) at 0° C. was added nBuLi (0.54 mL, 2.5M in hexanes, 1.35 mmol). The reaction mixture was stirred for 30 minutes at 0° C., at which point a solution of p-toluenesulfonyl chloride (258 mg, 1.35 mmol) in THF (5 mL) was added via syringe. The reaction mixture was stirred for 1 hour at 0° C. and nBuLi (0.54 mL, 2.5M in hexanes, 1.35 mmol) was added. The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl ether (100 mL) and washed with water (50 mL). The aqueous layer was extracted with ethyl ether (2×50 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 477 mg cloudy beige oil. The crude oil was purified by flash chromatography (12 g silica, 0-50% ethyl acetate/heptane, 26 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a colorless oil (258 mg, 57% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27][C:28](O)=[O:29])[CH:17]=[N:16]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(=O)(O)[O-].[Na+].C(OC(C)C)(=O)C>O1CCCC1.C(N(CC)CC)C>[CH:6]1([N:5]([CH2:4][CH:3]([O:12][CH3:13])[O:2][CH3:1])[C:28](=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23][C:22]2[CH:31]=[CH:32][CH:33]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=3)[CH:21]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Reactant: COC(CNC1CCCCC1)OC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)C
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCC1)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of N-(2,2-dimethoxyethyl)cyclohexanamine (21.5 g) in tetrahydrofuran (30 mL) was added to a solution of 3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid in tetrahydrofuran (105 mL) at 20° C. Tetrahydrofuran (15 mL) was added, followed by triethylamine (51.8 mL), followed by a solution of T3P in tetrahydrofuran (121.9 mL of a 1.62M solution). The solution was stirred at 20° C. for 1 h then cooled to 10° C. Pre-chilled (10° C.) 0.5M sodium bicarbonate solution (225 mL) was added, followed by iso-propyl acetate (150 mL). After mixing the layers were separated and the organic layer washed with 20% w/w sodium chloride solution (150 mL), then evaporated to dryness to afford the subtitled compound as a brown oil (48.6 g). MS [M+H-MeOH]+=412.20 (100%) (MultiMode+) [M+H]+=444.20 (MultiMode+) 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.62 (s, 1H), 7.33-7.23 (m, 3H), 7.10-7.03 (m, 1H), 4.61 (t, 0.7H), 4.36 (t, 0.3H), 3.94 (s, 3H), 3.79 (q, 2H), 3.69 (q, 2H), 3.62-3.43 (m, 1.5H), 3.40 (s, 3H), 3.38 (s, 3H), 3.30 (d, 1.5H), 2.89 (q, 2H), 2.69 (quintet, 2H), 1.86-0.99 (m, 10H); approx:2:1 ratio of rotamers
Reaction SMILES: Br[C:2]1[CH:42]=[CH:41][C:5]2[N:6]=[C:7]([N:23]([C:32]3[C:37]([Cl:38])=[CH:36][C:35]([F:39])=[CH:34][C:33]=3[Cl:40])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:8]3[CH:9]=[CH:10][N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[NH2:43][CH2:44][CH:45]([C:47]1[CH:52]=[N:51][CH:50]=[CH:49][N:48]=1)[OH:46].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[Cl:38][C:37]1[CH:36]=[C:35]([F:39])[CH:34]=[C:33]([Cl:40])[C:32]=1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:7]1[C:8]2[CH:9]=[CH:10][N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:22])[CH3:20])[C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2]([NH:43][CH2:44][CH:45]([OH:46])[C:47]3[CH:52]=[N:51][CH:50]=[CH:49][N:48]=3)[CH:42]=[CH:41][C:5]=2[N:6]=1
Reactant: NCC(O)c1cnccn1
Reactant: C[Si](C)(C)CCOCN(c1c(Cl)cc(F)cc1Cl)c1nc2ccc(Br)cc2c2c(=O)n(COCC[Si](C)(C)C)ccc12
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCN(c1c(Cl)cc(F)cc1Cl)c1nc2ccc(NCC(O)c3cnccn3)cc2c2c(=O)n(COCC[Si](C)(C)C)ccc12
Temperature: 100 °C

Procedure:
To a solution of 9-bromo-5((2,6-dichloro-4-fluorophenyl){[2-(trimethylsilyl)ethoxy]methyl}amino)-2-{[2-(trimethylsilyl)ethoxy]methyl}benzo[c]-2,6-naphthyridin-1(2H)-one (Example 172, Step 1) (50 mg, 0.07 mmol) and 2-amino-1-pyrazin-2-ylethanol (14.6 mg, 0.11 mmol) in DMSO (1 ml) was added L-proline (2 mg, 0.014 mmol), potassium carbonate (29.7 mg, 0.14 mmol) and CuI (1.3 mg, 7.01 μmol). The solution was heated to 100° C. in a sealed tube for 16 h. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with water. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:26]=[CH:25][C:17]3[CH2:18][CH2:19][CH2:20][N:21](C=O)[CH2:22][C:16]=3[CH:15]=2)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl>CO>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:26]=[CH:25][C:17]3[CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:16]=3[CH:15]=2)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CN(C=O)CCC3)CC1
Agent: Cl
Solvent: CO
Product: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CNCCC3)CC1
Temperature: 82.5 °C
Yield: 73.1 %

Procedure:
A solution of 3-(1-acetyl-4-piperidinyl)-1-(2-formyl-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl)-1-propanone (7.03 g, 20.5 mmol), prepared in 1), in methanol (100 ml) was mixed with concentrated hydrochloric acid (100 ml) and the mixture was heated at 80-85° C. for 1 hour. The methanol was then distilled off and the residual aqueous solution was made basic with NaOH/H2O and extracted with ethyl acetate-tetrahydrofuran (2:1). The extract was washed with saturated NaCl/H2O and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 3-(1-acetyl-4-piperidinyl)-1-(2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl)-1-propanone (4.92 g) as light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[O:22][CH:23]1[CH2:32][CH2:31][C:26]2(OCC[O:27]2)[CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>Cl.CC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[O:22][CH:23]1[CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32]1
Reactant: COc1ccc(Cn2ccc3cc(OC4CCC5(CC4)OCCO5)c(Cl)cc3c2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(Cn2ccc3cc(OC4CCC(=O)CC4)c(Cl)cc3c2=O)cc1
Yield: 69.8 %

Procedure:
1.00 g (2.19 mmol) of 7-chloro-6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (65) were stirred in 9 ml of 6 N HCl/acetone (1:2) at room temperature. After 2 h the reaction mixture was poured on saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried with magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography to give 630 mg of the title compound. Rt=1.81 min (Method B). Detected mass: 412.2 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([Sn](CCCC)(CCCC)COCC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)CCC.C(OCC)C.[F-].[K+]>C(Cl)(Cl)Cl>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:9])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [F-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(=O)C(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
Diphenylacetyl chloride (4.6 g), tri-n-butyl-((3,5-bis(trifluoromethyl)phenyl)methyloxymethyl)tin (12.6 g; Example 1a, (Method Ai)and benzylchlorobis(triphenylphosphine) palladium (II)(80 mg)were dissolved in chloroform (10 ml) and the solution heated at 80° C. for 6h. On cooling diethyl ether and saturated aqueous potassium fluoride were added and after 30 minutes the solution was filtered through Hiflo™. The organic layer was washed with water, saturated brine and dried (MgSO4). After evaporation in vacuo the residual oil was purified by chromatography on silica gel (eluting with 0 to 10% ethyl acetate in petroleum ether bp=60°-80° C.) to give 1-(3,5-bis(trifluoromethyl)phenyl)methyloxy)-3,3-diphenyl acetone as an oil. 1H NMR (CDCl3, 360MHz) δ7.80 (1H; s; 4-aryl CH) 7.71 (2H; s; 2,6-aryl CH), 7.43-7.24 (10H; m; phenyl), 5.30 (1H; s; Ph2CH), 4.56 (2H; s), 4.31 (2H; s). m/e Found 452.1191, C24H13F6O2 requires 452.12110.