Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][C:36]([OH:38])=O)[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH:41]([NH2:44])([CH3:43])[CH3:42].C(OCC)(=O)C>CN(C)C=O>[F:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][C:36](=[O:38])[NH:44][CH:41]([CH3:43])[CH3:42])[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
Under ice cooling, 1,1′-carbonyldimidazole (15 g) was added to a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (30 g) in dimethylformamide (240 ml) and the resultant mixture was stirred for 2 hr. After adding isopropylamine (5.6 g), the mixture was warmed to room temperature and then stirred for additional 2 hr. Next, ice water (240 ml) and ethyl acetate (300 ml) were added to the reaction solution and the layers were separated. The organic layer was washed successively with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in hot ethyl acetate (80 ml). After allowing to cool to room temperature, the resulting crystals were collected by filtration to give the title compound (17.2 g) as a white powder (yield: 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][O:58][CH:59]1[CH2:63][CH2:62][N:61]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([CH2:71][NH:72][CH3:73])=[CH:67][CH:66]=2)[CH2:60]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:72]([CH2:71][C:68]3[CH:67]=[CH:66][C:65]([CH2:64][N:61]4[CH2:62][CH2:63][CH:59]([O:58][CH3:57])[CH2:60]4)=[CH:70][CH:69]=3)[CH3:73])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(OC)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(OC)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.11 mmol), EDCI (30 mg, 0.15 mmol), HOBt (23 mg, 0.17 mmol), DIPEA (0.04 mL, 0.23 mmol) and 1-{4-[(3-methoxypyrrolidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (37 mg, 0.13 mmol) in DCM (10 mL).
Reaction SMILES: C(O)(=O)C.Br.C(OP([N:14]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:24][CH2:23][CH2:22][CH:21]([F:40])[CH2:20][CH2:19][CH2:18][N:17]([S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[N+:50]([O-:52])=[O:51])(=[O:43])=[O:42])[CH2:16][CH2:15]1)(=O)OCC)C>C(OCC)C>[F:40][CH:21]1[CH2:22][CH2:23][CH2:24][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:29])=[O:30])[CH2:26][CH2:27][NH:14][CH2:15][CH2:16][N:17]([S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[N+:50]([O-:52])=[O:51])(=[O:42])=[O:43])[CH2:18][CH2:19][CH2:20]1
Reactant: CCOP(=O)(OCC)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCCC(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCC(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
Acetic acid (15 ml), saturated with anhydrous hydrogen bromide (gas) was added to [11-fluoro-1,7-bis(2-nitro-benzenesulfonyl)-1,4,7-triaza-cyclotetradec-4-yl]-phosphonic acid diethyl ester (560 mg, 0.77 mmol) contained in round-bottomed flask closed by glass stopper. The resulting mixture was allowed to stir for 18 hours at room temperature and then diethyl ether (50 ml) was added. The white precipitate which formed was allowed to settle to the bottom of the flask and the diethyl ether solution was decanted off. This white solid was re-dissolved in methanol, stirred with K2CO3 (solid) for 30 mins then diluted with 100-ml ethyl acetate, and the solids were removed by filtration. Evaporation of the filtrates gave the title compound (454 mg, 100%) as white foam. 1H NMR (CDCl3) δ 1.75–1.99 (m, 8H), 2.90 (t, 4H, J=5.0 Hz), 3.26–3.39 (m, 8H), 4.61–4.77 (m, 1H), 7.60–7.65 (m, 2H), 7.68–7.72 (m, 4H), 7.94–7.97 (m, 2H); ES-MS m/z 588.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].[CH3:26]I.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]([CH3:26])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:16])[Cl:17])=[O:12])[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](N(C)C(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4S)-4-(2,2,2-trichloro-ethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (420 mg, 1 mmol) and methyl iodide (0.18 mL, 3 mmol) in DMF (10 mL) cooled at 0° C. under argon was added sodium hydride (44 mg, 1.1 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water. The desired compound was extracted with EtOAc (2×25 mL), the organic phases were joined, washed with 1N HCl then brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). MS (UPLC): 436 [M+H]+, 434 [M−H]−; tR (HPLC conditions f): 2.35 min.
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].O.O.O.[C:15]([O-])(=[O:17])[CH3:16].[Na+].C(OC(=O)C)(=O)C>>[C:15]([NH:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2]1)(=[O:17])[CH3:16]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1Cc2ccccc2C1

Procedure:
25 g. of 2-indanamine hydrochloride (0.15 mole), 20 g. of sodium acetate trihydrate (0.14 mole), and 40 g. of acetic anhydride (0.4 mole) were stirred at 25° C. for sixteen hours. The mixture was evaporated and the residue was partitioned between chloroform and water. The chloroform extracts were pooled, washed with 10% hydrochloric acid and then with 5% aqueous sodium carbonate, dried and evaporated to yield N-acetyl-2-indanamine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]2[CH:13]=[N:14][N:15]=[C:11]2[C:10]2[CH:9]=[C:8]([CH3:16])[CH:7]=[CH:6][C:5]=2[N:4]=1.[OH-:17].[Na+].Cl>O1CCOCC1>[CH3:16][C:8]1[CH:7]=[CH:6][C:5]2[NH:4][C:3](=[O:17])[CH2:2][N:15]3[N:14]=[CH:13][N:12]=[C:11]3[C:10]=2[CH:9]=1
Reactant: Cc1ccc2nc(CCl)n3cnnc3c2c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)-c1ncnn1CC(=O)N2
Temperature: 8 °C
Reaction time: 0.17 h

Procedure:
5. 62.1 g of 5-(chloromethyl)-9-methyl-1,2,4-triazolo[4,3-c]quinazoline are suspended in 1.1 l of dioxan and cooled to 8° C. 320 ml of 1N sodium hydroxide solution are added dropwise thereto within 10 min. at 7° to 10° C. The mixture is stirred at room temperature for 24 h. The reaction mixture is then made weakly acid (pH 5-6) with 2N hydrochloric acid and concentrated in a vacuum. The residue is dissolved in dichloromethane and washed with sodium chloride solution. The organic phase is dried, decolorized with Norit charcoal, filtered clear and concentrated in a vacuum to a volume of about 400 ml. After the addition of 400 ml of ethyl acetate the mixture is again concentrated to a volume of about 200 ml. The crystal slurry is left to stand at -25° C. overnight and the crystals are then filtered off. After drying in a vacuum there are obtained 35.5 g of 10-methyl-5H-[1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one of m.p. 206°-208° C.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12]([N:14]1[CH2:20][C:16]2([CH2:19][NH:18][CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[CH2:36][N:37]=[C:38]=[O:39]>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:15][C:16]2([CH2:17][N:18]([C:38](=[O:39])[NH:37][CH2:36][C:30]3[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=3[Cl:28])[CH2:19]2)[CH2:20]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2(CN(C(=O)NCc3ccc(Cl)cc3Cl)C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a stirred solution of 6-(tert-butoxycarbonyl)-2,6-diaza-spiro[3.3]heptane oxalate (200 mg, 1.01 mmol) in dichloromethane (10 mL) was added triethylamine (141 μl, 1.01 mmol) followed by 2,4-dichloro-1-(isocyanatomethyl)benzene (204 mg, 1.01 mmol). The reaction mixture was stirred at ambient temperature for 1 h. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2; methanol:dichloromethane 0:1 to 1:9) to give the title compound (344 mg, 85%) as a white solid. MS (EI) m/e: 400.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:7])[CH2:4][O:5][CH3:6].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.O>C1C=CC=CC=1>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]2[NH:1][CH2:2][CH:3]([CH2:4][O:5][CH3:6])[O:7]2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COCC(O)CN
Solvent: c1ccccc1
Solvent: O
Product: COCC1CNC(c2ccc(Cl)cc2)O1
Temperature: 25 °C

Procedure:
Twelve and six tenths (12.6) grams of 1-amino-3-methoxy-2-propanol and 16.9 grams of p-chlorobenzaldehyde were combined in 150 milliliters of benzene and heated to reflux under a modified Dean-Stark apparatus until about 2.5 milliliters of water were azeotropically removed. An additional 50 milliliters of benzene was distilled over and the mixture was cooled to room temperature and the volume was adjusted to 109.2 milliliters, so that 4 milliliters=1 gram of intermediate. Aliquots of this solution were used in subsequent reactions.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH3:10])=[O:4].[Li]CCCC.C1COCC1.C(#N)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C1COCC1>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:1]2[NH:2][C:3](=[O:4])[C:5]3[CH:9]=[CH:8][S:7][C:6]=3[CH:10]=2)=[CH:23][CH:24]=1
Reactant: CNC(=O)c1ccsc1C
Reactant: COc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3sccc3c(=O)[nH]2)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of N-methyl-2-methylthiophene-3-carboxamide (36.0 g) in THF (500 ml) was added dropwise 2.5M n-BuLi/THF solution (200 ml) at −70° C. The reaction solution was stirred at −70° C. for 2 hr, followed by the addition of anisonitrile (31.0 g) at once. After the dry ice/acetone bath was removed, the reaction mixture was back to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride and ether were added thereto, and then the mixture was further stirred for 1 hr. The resulting white precipitates were collected by filtration, washed with water, ether and n-hexane in this order, and then dried, to give the title compound (17.9 g, yield; 30%).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:25])[CH2:14][CH2:15][C:16](=[N:17][NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])C.O.[NH2:27][NH2:28]>C(O)C>[C:19]1([NH:18][N:17]=[C:16]2[C:9]3=[N:8][CH:7]=[C:6]([C:4]([NH:27][NH2:28])=[O:5])[C:11](=[O:12])[N:10]3[CH:13]([CH3:25])[CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2=NNc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1CCC(=NNc2ccccc2)c2ncc(C(=O)NN)c(=O)n21
Yield: 82.7 %

Procedure:
7.8 g. (0.02 mole) of ethyl-9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate are dissolved in 100 ml. of ethanol. To the solution 6.0 ml. of 98% hydrazine-hydrate are added and the reaction mixture is refluxed for 2 hours. On cooling the precipitation of crystals begins. The crystals are filtered off and washed with ethanol. Thus 5.4 g. (82.7%) of 9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-prido(1,2-a)pyrimidine-3-carbohydrazide are obtained. Mp.: 205°-207° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
100 mg (72%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272 mmol), 1-(4-chlorophenyl)piperazine (73 mg, 0.272 mmol), DIPEA (0.071 mL, 0.408 mmol) and NaBH(OAc)3 (173 mg, 0.816 mmol).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31]C6CCCCO6)[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl>CO.O1CCOCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][OH:31])[CH2:27][CH2:28]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCOC4CCCCO4)CC3)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCO)CC3)cc1OCC2
Reaction time: 0.75 h
Yield: 30.5 %

Procedure:
A solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (371 mg, 0.73 mmol) in methanol (3.5 mL) was treated with 4N HCl in dioxane (3.5 mL) and the mixture stirred for 45 min before being concentrated in vacuo. The resultant residue was re subjected to the reaction conditions as before and stirred for 1 h at RT before being concentrated in vacuo. The resultant residue was partitioned between DCM/saturated aqueous sodium hydrogen carbonate, the aqueous extracted twice with DCM and the combined organic extracts washed with brine and then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, column preconditioned with 1% TEA in DCM, gradient 0 to 7% methanol in DCM) to give 293 as a yellow foam (94 mg, 30%). LCMS: RT=2.61 min, [M+H]+=423. 1H NMR 400 MHz (DMSO-d ) δ: 8.32 (1 H, d, J=8.28 Hz), 7.89 (2 H, d, J=1.96 Hz), 7.05 (1 H, dd, J=8.31, 1.76 Hz), 6.89 (1 H, d, J=1.71 Hz), 5.88-5.87 (1 H, m), 4.49 (4 H, q, J=5.91 Hz), 3.53 (2 H, t, J=7.21 Hz), 3.03 (2 H, d, J=11.27 Hz), 2.52 (3H, m), 2.16 (2 H, t, J=11.38 Hz), 1.76 (2 H, d, J=12.61 Hz), 1.67 (2 H, d, J=12.75 Hz), 1.47 (6 H, d, J=6.60 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([O:20][CH3:21])=[O:19].[CH3:22][C:23]1[CH:27]=[C:26]([CH2:28][C:29](O)=[O:30])[O:25][N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=2)=[CH:4][C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:26]2[O:25][N:24]=[C:23]([CH3:22])[CH:27]=2)[CH:7]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1NC(=O)Cc1cc(C)no1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.8 %

Procedure:
To a solution of methyl 4-amino-6-chloro-4′-(dimethylamino)-[1,1′-biphenyl]-3-carboxylate (Intermediate 47) (10.8 g, 35.4 mmol) in dichloromethane (525 mL) was added 2-(3-methylisoxazol-5-yl)acetic acid (Aldrich, 5 g, 35.4 mmol), HATU (17.52 g, 46.1 mmol) and triethylamine (11.85 mL, 85 mmol) and the reaction mixture was stirred at room temperature for 72 h. The mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with hot methanol, filtered and dried to give the title compound methyl 6-chloro-4′-(dimethylamino)-4-(2-(3-methylisoxazol-5-yl)acetamido)-[1,1′-biphenyl]-3-carboxylate (13.91 g, 32.5 mmol, 92% yield) as a beige solid. LCMS: (M+H)+=428; Rt=3.86 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([OH:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl>CC(C)=O>[Br:1][C:2]1[C:3]([O:11][CH2:18][O:19][CH3:20])=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: COc1ccc(Br)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1c(Br)ccc(OC)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
To a stirring solution of 3-bromo-6-methoxybenzene-1,2-diol (500 mg, 2.27 mmol) in acetone (40 mL) at 0° C. was added potassium carbonate (313 mg, 2.27 mmol) and methoxymethyl chloride (183 mg, 2.27 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-8% ethyl acetate in pet ether) afforded 3-Bromo-6-methoxy-2-(methoxymethoxy)phenol as a liquid (230 mg, 38%).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[Cl:29]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([N:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[C:28]([Cl:29])[CH:27]=3)[C:11]=2[O:10][CH2:9]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N1COc2c(Br)cccc2C1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)N1COc2c(cccc2-c2ccc(Cl)c(Cl)c2)C1
Temperature: 58.5 °C
Reaction time: 2.5 h
Yield: 54.4 %

Procedure:
A mixture of 8-bromo-3-(tert-butyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.46 g, 1.71 mmol), potassium carbonate (0.945 g, 4.0 equiv), 3,4-dichlorophenylboronic acid (0.489 g, 1.5 equiv), and tetrakis(triphenylphosphine)Pd (0) (63 mg, 3.2 mol %) was heated at 53-64° C. for 3 hours, then at 80-87° C. for 2.5 hours. To the mixture was added additional 3,4-dichlorophenylboronic acid (0.2 g) and the resulting mixture was heated at 80-87° C. overnight. Upon cooling to room temperature, the reaction mixture was concentrated. The crude product was purified by column chromatography to give 3-(tert-butyl)-8-(3,4-dichlorophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.313 g) as yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:8][C:3]1[C:2]([C:11]2[CH2:12][CH2:13][CH2:14][C:9](=[O:15])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: O=C1C=CCCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2F)CCC1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-2-fluoropyridine (11 g, 62.5 mmol), 2-cyclohexen-1-one (24.03 g, 250 mmol), N,N-dicyclohexylmethylamine (30.5 g, 156 mmol) and bis(tri-t-butylphosphine)palladium (o) (0.958 g, 1.875 mmol) in dioxane (80 mL) was heated to 105° C. for 6 h. The mixture was cooled to RT and the dioxane was evaporated under reduced pressure. Water (200 ml) was added and the mixture layer was extracted with EtOAc (2×200 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (20% to 50% EtOAc in hexanes) afforded 3-(2-fluoropyridin-3-yl)cyclohex-2-enone as colorless crystals. MS (ESI, pos. ion) m/z: 191.9 (M+1).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CS(C)=O>[C:32]([O:31][C:30]([N:29]([C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[F:21])[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:3]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)c1ccc(Cl)nc1-c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N(C(=O)OC(C)(C)C)c2c(F)cccc2F)nc1-c1ccc(F)cc1F
Temperature: 57.5 °C
Reaction time: 48 h

Procedure:
A mixture of Compound 5 (100.82 g, 0.33 mol, 1.0 equiv.), Compound 7 (101.05 g, 0.44 mol, 1.30 eq), and cesium carbonate (177.12 g, 0.54 mol, 1.60 eq) was suspended in DMSO (250 mL, 2.5 volumes) and stirred vigorously at 55-60° C. for 48 hours (completeness of reaction determined by HPLC). The mixture was cooled to 20-30° C. and the base was quenched by careful and slow addition of a 1 N HCl (aq) solution (540 mL, 1.60 eq), keeping the internal temperature of the reaction mixture below 30° C. Upon cooling, a precipitate formed and was filtered and washed with water (2×250 mL, 2×2.5 volumes). The precipitate was then suspended in absolute ethanol (1000 mL, 10 volumes) and heated to reflux. The reflux was maintained for 30-60 minutes, and water (200 mL, 2 volumes) was added to the mixture. The resulting mixture was then heated again to reflux, and reflux was maintained for 30 minutes, at which point the suspension was cooled to 10° C. The resulting solids were then filtered and washed with water (2×250 mL, 2×2.5 volumes), followed by absolute ethanol (250 mL, 2.5 volumes), and then transferred to a vacuum oven and dried at 50-60° C. The title Compound, 8, was obtained as a white crystalline solid. (1H NMR, 500 MHz; CDCl3) δ 8.28 (d, 1H), 8.12 (d, 1H), 7.19 (q, 1H), 6.96 (t, 2H), 6.81 (t, 1H), 6.74 (t, 1H), 4.25 (q, 2H), 1.50 (s, 9H), 1.20 (t, 3H).