Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:17]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46].Cl>ClCCl.CO>[ClH:29].[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:17]=2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 141.6 %

Procedure:
Following general procedure F, 1-(6-bromo-4-(3-(2-(pyrrolidin-1-yl)ethyl)phenylamino)quinolin-3-yl)ethanone (5.7 g, 13.0 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.1 g, 14.2 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 100 mL) after which HCl (40 mL, 1.25 M in methanol) was added to form a solution. The solution was concentrated to dryness and the resultant solid was triturated with acetonitrile. The mixture was filtered, washed with acetonitrile, and dried to obtain desired product (5.6 g, 73% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.31 (s, 1H), 8.19 (dd, J=8.8, 2.0 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.75-7.55 (m, 3H), 7.53 (s, 1H), 7.43-7.34 (m, 1H), 7.10 (s, 2H), 3.66 (br s, 2H), 3.48-3.36 (m, 2H), 3.24-3.06 (m, 4H), 2.82 (s, 3H), 2.07 (br s, 4H); APCI MS m/z 520 [C29H27Cl2N3O2+H]+; HPLC>99% (AUC), tR=9.17 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1)=[O:16]>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:29]=[CH:28][CH:27]=[C:14]([C:15]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][C:22](=[O:26])[NH:23]3)=[CH:19][CH:18]=2)=[O:16])[CH:13]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A dry flask was charged with 2-Methyl-benzoyl chloride (3.00 g, 19.41 mmol) and THF (200 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 4.895 g, 19.4 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF (15 mL) and collected to afford the 2-Methyl-N-[3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-benzamide as a solid (5.174 g, 13.97 mmol, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Yield: 63.2 %

Procedure:
(S)-3-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (65 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (46 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].[C:8](#N)[CH3:9]>[Co]>[CH3:8][CH:9]1[NH:7][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2][NH:1]1
Reactant: CCC(N)CCN
Reactant: CC#N
Agent: [Co]
Product: CCC1CCNC(C)N1
Temperature: 90 °C
Reaction time: 5 h
Yield: 96.2 %

Procedure:
Ninety grams (96.8% purity, 0.854 mole) 1,3-diaminopentane, 60 g acetonitrile (1.46 moles) and 3 g Cr promoted Raney® cobalt catalyst were charged to a 300 ml autoclave described in Example 1. The mixture was stirred and heated at 90° C. and 650 psig pressure for 5 hours followed by cooling to 25° C. Analysis of the filtered product on a capillary GC column showed a 14% conversion of 1,3-diaminopentane and 96.2% yield of 2-methyl-4-ethylhexahydropyrimidine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:20][CH2:21][NH:22][CH:23]([CH3:25])[CH3:24])([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:9]([NH2:11])=[O:10].[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([N:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:20][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:9]([NH2:11])=[O:10])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)NCCC(CCN1CCCCC1)(C(N)=O)c1ccccc1Cl
Product: CC(=O)N(CCC(CCN1CCCCC1)(C(N)=O)c1ccccc1Cl)C(C)C

Procedure:
acetylating α-(2-chlorophenyl)-α-[2-[(1-methylethyl)amino]ethyl]-1-piperidinebutanamide in the presence of acetic anhydride to give α-[2-[acetyl (1-methylethyl)amino]ethyl]-α-(2-chlorophenyl)-1-piperidinebutanamide.
Reaction SMILES: [Cl:1]NC(=O)CCC(N)=O.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24]([OH:26])=[C:23]([C:27]#[N:28])[C:22](=[O:29])[NH:21][C:20]=3[S:19][CH:18]=2)=[CH:13][CH:12]=1>C(O)(=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:24]([OH:26])=[C:23]([C:27]#[N:28])[C:22](=[O:29])[NH:21][C:20]=3[S:19][C:18]=2[Cl:1])=[CH:15][CH:16]=1
Reactant: N#Cc1c(O)c2c(-c3ccc(Br)cc3)csc2[nH]c1=O
Reactant: NC(=O)CCC(=O)NCl
Solvent: CC(=O)O
Product: N#Cc1c(O)c2c(-c3ccc(Br)cc3)c(Cl)sc2[nH]c1=O
Temperature: 90 °C

Procedure:
N-chlorosuccinamide (1.56 mmol, 0.2 g) was added to a solution of 3-(4-bromophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (1 mmol, 0.350 g) in acetic acid (5 mL) at room temperature. The reaction was heated at 90° C. for 5 h, cooled and quenched with water (30 mL). The aqueous mixture was extracted with ethyl acetate (3×30 mL), dried (Na2SO4), concentrated and purified on RP-HPLC to afford the title compound. MS (ESI) m/e 381 (M−H)+; 1H NMR (500 MHz, DMSO-d6): δ ppm 11.93 (br s, 1H), 7.59 (d, J=10, 2H), 7.28 (d, J=10, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH2:16][C:15]3=[O:31])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:34]=O>C(O)=O>[CH3:34][N:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)[N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]=[CH2:30])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH2:16][C:15]1=[O:31]
Reactant: C=O
Reactant: C=Cc1ccc(S(=O)(=O)N2CCN(NC3CCN(c4ccncc4)CC3)C(=O)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: C=Cc1ccc(S(=O)(=O)N2CCN(N(C)C3CCN(c4ccncc4)CC3)C(=O)C2)cc1
Yield: 75 %

Procedure:
1-{[1-(4-pyridinyl)-4-piperidinyl]amino}-4-(4-vinylbenzenesulfonyl)-2-piperazinone (180 mg) was dissolved in a 37% aqueous solution of formaldehyde (11 ml and formic acid (5 ml) and refluxed for 2 hours. The reaction mixture was cooled and made alkaline by adding an aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and concentrated. The residue was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from ether to obtain the title compound (139 mg, 75%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][N:21]([C@@H:29]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH3:30])C(=O)OC(C)(C)C)[CH:16]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:15]1.Cl.O1CCOCC1>>[F:13][C:4]1[CH:5]=[C:6]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:7]=[C:2]([F:1])[C:3]=1[N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C@@H:29]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH3:30])[CH:16]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:15]1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2c(F)cc(-c3nnn[nH]3)cc2F)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(c2c(F)cc(-c3nnn[nH]3)cc2F)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To 205 mg of tert-butyl ({1-[2,6-difluoro-4-(1H-tetrazole-5-yl)phenyl]-3-phenylpiperidin-4-yl}methyl)[(1R)-1-(1-naphthyl)ethyl]carbamate was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was then added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 158 mg of (1R)—N-({1-[2,6-difluoro-4-(1H-tetrazol-5-yl)phenyl]-3-phenylpiperidin-4-yl}methyl)-1-(1-naphthyl)ethaneamine. 2.0 mL of hydrogen chloride/1,4-dioxane solution was added thereto, followed by concentration under reduced pressure, and to the obtained residue was then added about 3 mL of isopropanol, followed by heating. The mixture was left to be cooled to room temperature, and the precipitate was collected by filtration, and dried under reduced pressure to obtain 153 mg of (1R)—N-({1-[2,6-difluoro-4-(1H-tetrazol-5-yl)phenyl]-3-phenylpiperidin-4-yl}methyl)-1-(1-naphthyl)ethaneamine hydrochloride as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].[CH2:25]([NH2:28])[CH2:26][NH2:27].O>CS(C)=O.C(N(CC)C(C)C)(C)C>[NH2:1][C:2]1[N:23]=[C:22]([NH:27][CH2:26][CH2:25][NH2:28])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: NCCN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: NCCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 120 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (150 mg, 0.417 mmol) described in Preparation Example A+-11, ethane-1,2-diamine (418 μl, 6.25 mmol) were dissolved in a mixture solution of dimethylsulfoxide (2 mL) and N,N-diisopropylethylamine (1 mL), and the solution was stirred at 120° C. for 15 hours. The reaction solution was cooled to room temperature, water was added, then extracted with ethyl acetate and tetrahydrofuran, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, tetrahydrofuran and NH silica gel were added to the residue, the solvent was evaporated in vacuo adsorption, purification was carried out by NH silica gel column chromatography (ethyl acetate:methanol=10:1), and the title compound (95 mg, 0.25 mmol, 59%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12](=[CH2:17])[C:13]([O:15][CH3:16])=[O:14])=[N:9][C:8]([O:18][CH3:19])=[CH:7][CH:6]=2.CC([N:24]([CH2:28][C@@H:29]1[O:34][CH2:33][CH2:32][NH:31][CH2:30]1)[C:25](=[O:27])[O-:26])(C)C>>[CH3:2][C:11]([O:26][C:25]([NH:24][CH2:28][C@@H:29]1[O:34][CH2:33][CH2:32][N:31]([CH2:17][CH:12]([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:18][CH3:19])[N:9]=3)[N:4]=[CH:3][C:2]=2[F:1])[C:13]([O:15][CH3:16])=[O:14])[CH2:30]1)=[O:27])([CH3:12])[CH3:10]
Reactant: CC(C)(C)N(C[C@H]1CNCCO1)C(=O)[O-]
Reactant: C=C(C(=O)OC)c1c(F)cnc2ccc(OC)nc12
Product: COC(=O)C(CN1CCO[C@@H](CNC(=O)OC(C)(C)C)C1)c1c(F)cnc2ccc(OC)nc12
Yield: 100 %

Procedure:
This compound was prepared from methyl 2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-propenoate and 1,1-dimethylethyl[(2R)-2-morpholinylmethyl]carbamate according to the general method of Example 2(d), in 100% yield.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=2[CH:7]=O)[CH2:3][CH2:2]1.[C:16]([S@@:20]([NH2:22])=[O:21])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[CH:1]1([S:4][C:5]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=2/[CH:7]=[N:22]/[S@:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:21])[CH2:3][CH2:2]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1SC1CC1
Reactant: CC(C)(C)[S@@](N)=O
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cc([N+](=O)[O-])ccc1SC1CC1
Temperature: 73 °C
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
To 76A (2.02 g, 9.0 mmol), (S)-tert-butylsulfinamide (1.21 g, 10 mmol) in CH2Cl2 (40 mL) was added Ti(OEt)4 (10 mL, 45 mmol). The mixture was heated at 73° C. for 6.0 h. CH2Cl2 was removed under vacuo and the residue was suspended in EtOAc. To this suspension was added brine. The mixture was stirred at rt for 15 min before it was filtered through a pad of wet Celite®. The filtrate was extracted with EtOAc (3×50 mL). The organic layer was washed with brine and dried over Na2SO4. After removal of solvent, 85A (3.0 g, 100% yield) was obtained as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.72-0.81 (m, 2H) 1.21 (m, 2H) 1.28 (s, 9H) 2.14-2.21 (m, 1H) 7.89 (d, J=8.79 Hz, 1H) 8.24 (dd, J=8.79, 2.64 Hz, 1H) 8.60 (d, J=2.64 Hz, 1H) 8.77 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[C:14]([C:15]=1[O:16]C(=O)C)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].CCCCO.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2ccccc2c1OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CCOC(=O)c1nc(-c2ccccc2)c2ccccc2c1O
Reaction time: 4 h

Procedure:
A mixture of 4-acetoxy-1-phenyl-isoquinoline-3-carboxylic acid ethyl ester (671 mg, 2 mmol; can be obtained according to D. A. Walsh et al. in J. Med. Chem. 1978, 21, 582-585), n-BuOH (60 ml) and concentrated H2SO4 (1.7 ml) was refluxed with stirring for 4 h before the reaction mixture was added to concentrated aqueous NaHCO3 solution (60 ml) with stirring. Then EtOAc (120 ml) was added and the mixture was stirred vigorously for 15 min. Subsequently, the organic phase was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silca gel using hexanes:EtOAc=95:5 as the eluent gave the title compound as a solid (126 mg); 1H NMR (CDCl3): δ=11.96 (s, 1H), 8.44 to 8.49 (m, 1H), 8.01 to 8.05 (m, 1H), 7.43 to 7.80 (m, 7H), 4.56 (q, 2H), 1.49 (t, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:16]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([F:21])=[CH:19][CH:20]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2ccccc2)c1
Yield: 26.1 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (750 mg, 1.95 mmol), phenyl boronic acid (418 mg, 4.87 mmol) and palladium (II) acetate gave the title compound as a white solid (195 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 2H), 7.46-7.38 (m, 3H), 7.35 (dd, J=4.3, 11.7 Hz, 2H), 7.08 (dd, J=8.6, 10.1 Hz, 1H), 5.10 (s, 1H), 4.60 (s, 1H), 3.33-2.10 (m, 6H), 1.67 (d, J=7.9 Hz, 6H), 1.67 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 159.9, 157.4, 136.2, 129.3, 129.0, 128.7, 127.9, 127.6, 125.7, 125.6, 71.0, 66.1, 55.7, 55.1, 47.5, 46.6, 29.9, 29.6, 25.5, 24.5, 19.5, 15.5 ppm. Purity: 98% UPLCMS (210 nm); retention time 0.95 min; (M+1) 382.9. Anal. Calcd. for C23H27FN2O2.0.29 (CHCl3): C, 67.08; H, 6.60; N, 6.72. Found: C, 67.09; H, 6.95; N, 6.37.
Reaction SMILES: [NH:1]1[C:10](=O)[CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=3[C:2]1=2.B.[OH-].[Na+].Cl>O1CCCC1.C(O)(=O)C.O>[NH:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=3[C:2]1=2
Reactant: O=C1CCc2ncc3ccccc3c2N1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc2c3c(ncc2c1)CCCN3
Temperature: 0 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A stirred solution of 1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one (4.0 g) in sieve dried tetrahydrofuran (400 ml) was treated over a few minutes with 0.98M borane in tetrahydrofuran (62 ml) under a dry nitrogen atmosphere. The resultant suspension was stirred for 5 hours at ambient temperature during which time a solution formed. After standing overnight at ambient temperature the solution was treated with glacial acetic acid (16 ml) followed by stirring for several minutes. The solution was then treated with 10% sodium hydroxide solution (180 ml) to give a biphasic system. Concentration on a rotary evaporator to remove the tetrahydrofuan gave a suspension of a solid which was extracted with CH2Cl2 (2×800 ml). The combined, dried (Na2SO4) organic phase was concentrated to afford a solid (5.18 g, tentatively identified as a borane complex). A suspension of the solid in glacial acetic acid (15 ml) was treated gradually with concentrated HCl (50 ml). When the gas evolution ceased, the mixture was warmed for a few minutes and then stirred for 0.5 hour at ambient temperature. The solution was strained through glass wool, and the filtrate was diluted with ice (300 ml) and water (100 ml) and then made alkaline with 50% sodium hydroxide solution. The mixture was extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated to dryness (3.7 g). Recrystallization from acetonitrile (20 ml) gave 1.97 g of a crystalline material which was combined with 2.01 g of a similarly prepared product. The material was purified by HPLC (silica gel, eluted with 5% methanol in ethyl acetate) to give 3.72 g of a solid. Recrystallization from acetonitrile (20 ml) afforded 3.01 g of crystals, m.p. 124.5°-127.5° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([CH2:25][CH3:26])[CH3:24]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([CH3:24])[CH2:25][CH3:26])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C)=NOCCO
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: CCC(C)=NOCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-butanone (2-hydroxyethyl) oxime, there is obtained 2-[(1-methylpropylideneamino)oxy]-ethyl 5,7- dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 351 (23), 281 (5), 237 (57), 194 (100), 114 (100), 70 (12);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.CCN(CC)CC.CN([CH:62]=[O:63])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH:62]=[O:63])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C=O)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 80 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (386 mg, 0.50 mmol) in DMF (10 mL) and Et3N (0.35 mL, 2.5 mmol) was added (n-octyl)3SiH (368 mg, 1.0 mmol). The mixture was degassed under 1 atm of CO balloon and PdCl2(PPh3)2 (72 mg, 0.10 mmol) was added, then degassed again with 1 atm of CO, and heated to 80° C. for 12 h. The reaction was cooled to RT and concentrated in vacuo. The residue was diluted with water then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Normal phase column chromatography on silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-formyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a light yellow solid contaminated with about 25% of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as by-product. The mixture was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]([CH3:59])([CH3:58])[CH2:13][N:14]1[C:26]2[C:25]3[CH:24]=[CH:23][C:22](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21][C:20]=3[N:19]=[C:18]([NH:34][C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]=2[N:16]=[C:15]1[CH2:54][O:55][CH2:56][CH3:57])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]([CH3:58])([CH3:59])[CH2:13][N:14]1[C:26]2[C:25]3[CH:24]=[CH:23][C:22]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21][C:20]=3[N:19]=[C:18]([NH:34][C:35]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]=2[N:16]=[C:15]1[CH2:54][O:55][CH2:56][CH3:57])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(/C=C/C(=O)OCC)ccc3c2n1CC(C)(C)OCCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)OCCNC(=O)OC(C)(C)C
Yield: 58 %

Procedure:
Palladium on carbon 10% (100 mg, 940 μmol) in ethanol (10 mL) was added to a suspension of (E)-ethyl 3-(1-(2-(2-(tert-butoxycarbonylamino)ethoxy)-2-methylpropyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl)acrylate (280 mg, 351 μmol) in ethyl acetate (30 mL). The mixture was stirred for 6 h in a hydrogen atmosphere at room temperature, filtered and solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel-NH2, 0% to 100% ethyl acetate in heptane) to give the title compound (0.163 g, 58%) as white solid; LC-MS (UV peak area, ESI) 74%, 800.5 (MH+).