Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C(NC2C=CC(N)=CC=2)=O)=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1C(O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(OC(N1C2C(=CC=CC=2)C=CC1)=O)C>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: CCOC(=O)N1CC=Cc2ccccc21
Agent: Nc1ccc(NC(=O)c2ccc(N)cc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 146.6 %

Procedure:
4-Amino-N-(4-amino-phenyl)-benzamide (3.00 g) and pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (6.55 g) were dissolved in DCM (90 mL), and 1-ethoxycarbonyl-1,2-dihydroquinoline (7.88 g) was added. The reaction mixture was stirred at ambient temperature for 17 hours and evaporated under vacuum. Oil was dissolved in ethyl acetate, forming a precipitate, which was collected by vacuum filtration and dried under vacuum, giving 2-(4-{-4-[(pyrrolidine-1′-carboxylic acid tert-butyl ester)-phenylcarbamoyl}-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.64 g, 93%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[N-:18]=[N+:19]=[N-:20].[Na+].C(O)(=O)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]2[NH:20][N:19]=[N:18][N:12]=2)=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(OCc2cccc(Cl)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(=O)O
Product: Clc1cccc(COc2ccc(-c3nnn[nH]3)cc2)c1

Procedure:
To a solution of 5×10-2 mole of 4-(3-chloro benzyloxy) benzonitrile in 20 ml of butanol are added 6.6×10-2 mole of sodium azide and 6.6×10-2 of acetic acid. Then the reaction mixture is heated to reflux for four days. 1 g of sodium azide, 2 g of acetic acid and 10 ml of butanol are added and the medium is again heated for two days at reflux. After concentrating by evaporating the solvent, the residue is taken up in 20 ml of 10% aqueous NaOH. After filtration, the aqueous phase is extracted with ether. By acidification of the alkaline solution using HCl 2N, the expected compound precipitates and is recrystallized in methanol.
Reaction SMILES: [CH2:1]([N:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:40])(=[O:39])[NH:34]C(C)(C)C)=[CH:23][CH:22]=1)[C:6]([N:8]([CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])=[O:7])[CH2:2][CH2:3][CH3:4]>CCCCCC.CCOC(C)=O>[CH2:1]([N:5]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:39])(=[O:40])[NH2:34])=[CH:25][CH:26]=1)[C:6]([N:8]([CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:16])[F:17])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N(C)c1ccccc1C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N(C)c1ccccc1C(F)(F)F
Yield: 76 %

Procedure:
The title compound was prepared from 1-butyl-1-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-3-methyl-3-[2-(trifluoromethyl)phenyl]urea (from Step B) according to the procedure of Example 2, Step D. Purification of the crude product by flash chromatography (elution with 2:1 and then 1:1 hexane-EtOAc) afforded a 76% yield of a stiff, white foam, which became tacky upon standing; homogeneous by TLC (3:1 hexane-EtOAc); FAB-MS m/e 521 (M+1)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([C:36]3[CH:41]=[CH:40][C:39]([O:42][Si](C(C)C)(C(C)C)C(C)C)=[CH:38][CH:37]=3)[C:31](=[O:35])[N:32]([CH2:33][CH3:34])[C:25]=12)(=[O:21])[CH3:20].[Cl-].[Cl-].[Ca+2]>C1COCC1>[C:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([C:36]3[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=3)[C:31](=[O:35])[N:32]([CH2:33][CH3:34])[C:25]=12)(=[O:21])[CH3:20]
Reactant: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(COC(C)=O)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(COC(C)=O)c21
Yield: 83.7 %

Procedure:
Tetrabutylammonium fluoride (1.241 mL) was added to a solution of [1-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methyl acetate (300 mg) in THF (dry) (1 ml) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20%-100% 50 EtOAc in hexane) to give [1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methyl acetate (170 mg) as a white solid.
Reaction SMILES: [CH:1](O)([OH:5])[C:2]#[C:3][CH3:4].[CH2:7]=[O:8].[CH:9]([OH:14])([OH:13])[CH2:10][CH2:11][CH3:12]>>[CH3:4][CH:3]([CH2:2][CH2:1][OH:5])[CH2:7][OH:8].[CH:9]([OH:14])([OH:13])[CH2:10][CH2:11][CH3:12]
Reactant: C=O
Reactant: CC#CC(O)O
Agent: CCCC(O)O
Product: CC(CO)CCO

Procedure:
As described in detail in copending application Ser. No. 924,212, filed July 12, 1978, (FDN-1113), the catalyst of the invention will produce high quality butanediol by a process involving a two-stage catalytic hydrogenation of a butynediol solution containing formaldehyde. During the first stage of the process, or low pressure, low temperature stage, a butanediol product having a much lower carbonyl number is obtained. The carbonyl number is the conventional measure of the undesired aldehyde and acetal content including residual formaldehyde. In the second or finishing stage, which is carried out at higher pressures and/or temperatures than the first stage, much less 2-methyl-1,4-butanediol byproduct (methylbutanediol) is produced concurrently with butanediol.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:45])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:45])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, undecanoyl chloride (0.45 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}undecanamide (0.53 g, 63%) as a white solid: mp 138-139° C.; 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 8.42 (t, J=5.9 Hz, 1H), 7.85-7.78 (m, 2H), 7.71-7.65 (m, 1H), 5.18-5.11 (dd, J=5.4 and 12.5 Hz, 1H), 4.72 (d, J=5.9 Hz, 2H), 2.96-2.83 (m, 1H), 2.64-2.47 (m, 2H), 2.18 (t, J=7.3 Hz, 2H), 2.08-2.04 (m, 1H), 1.55-1.50 (m, 2H), 1.24 (s, 14H), 0.85 (t, J=6.1 Hz, 3H); 13C NMR (DMSO-d6) δ 172.74, 172.63, 169.80, 167.47, 166.93, 139.55, 134.65, 133.10, 131.50, 127.04, 121.79, 48.83, 37.55, 35.21, 31.28, 30.92, 28.94, 28.74, 28.67, 25.20, 22.08, 21.97, 13.94; Anal. Calcd. For C25H33N3O5: C, 65.91; H, 7.30; N, 9.23. Found: C, 66.08; H, 7.13; N, 9.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(CCC(F)(F)F)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC(CCC(F)(F)F)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of 2-(3-chloro-phenyl)-5,5,5-trifluoro-pentanoic acid (1.75 g, 7 mmol) in tetrahydrofuran (40 ml) under an argon atmosphere was added slowly lithium aluminum hydride (0.4 g, 11 mmol) and the mixture was stirred for 17 hours at room temperature. For work-up water (1.5 ml) and 2N sodium hydroxide solution (0.5 ml) were added and the mixture was stirred for 30 min. After filtration the solvent was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1 to yield a colourless oil, (1.25 g, 75%); MS (EI): 311.0 ((M+OAc)+.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14](O)=[O:15])=[CH:11][C:10]=3[CH:17]=2)=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[OH:15][CH2:14][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:17][C:10]=2[CH:11]=1
Reactant: O=C(O)c1cc2cc(-c3ccsc3)ccc2o1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc2cc(-c3ccsc3)ccc2o1
Temperature: 5 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A solution of 5-thiophen-3-yl-benzofuran-2-carboxylic acid 21 (0.84 g, 3.4 mmole) dissolved in THF (30 ml) was cooled to 5° C., LiAlH4 (0.26 g, 6.9 mmole) was added portionwise. The solution was then stirred at ambient temperature for 2 hrs. After addition of 1M HCl, the mixture was extracted, washed, dried, evaporated, and the residue was purified by chromatography to give about 0.368 g of 2-hydroxymethyl-5-thiophen-3-yl-benzofuran 22, mp. 122–124° C.
Reaction SMILES: C([NH:8][C:9]1([CH2:13][CH:14]([OH:16])[CH3:15])[CH2:12][CH2:11][CH2:10]1)C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C:9]1([CH2:13][CH:14]([OH:16])[CH3:15])[CH2:12][CH2:11][CH2:10]1
Reactant: CC(O)CC1(NCc2ccccc2)CCC1
Agent: [Pd]
Solvent: CCO
Product: CC(O)CC1(N)CCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 94.1 %

Procedure:
10% Pd—C (300 mg) was added to a solution of 1-[1-(benzylamino)cyclobutyl]-2-propanol (2.24 g, 10.2 mmol) in EtOH (50 mL) and the mixture was stirred under H2 gas (5 kgf/cm2) at room temperature for 10 hours. The mixture was filtered and the filtrate was concentrated in vacuo. Distillation of the residue gave the title compound as a pale yellow oil (1.24 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[N:11][N:10]=1.Cl[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=3)[CH2:21][CH2:22]2)=[O:15])=[N:11][N:10]=1
Reactant: O=C(NC1CCNCC1)c1nnc(Nc2ccccc2F)o1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)nc1
Yield: 11.7 %

Procedure:
A solution of 5-[(2-fluorophenyl)amino]-N-piperidin-4-yl-1,3,4-oxadiazole-2-carboxamide (Intermediate 101) (100 mg, 0.33 mmol) and methyl 6-chloronicotinate (56 mg, 0.33 mmol) in dry DMF (3 mL) was heated in the microwave at 120° C. for 1 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to give the title compound (17 mg, 12%) as a solid; 1H NMR δ 1.66-1.53 (m, 2H), 1.92-1.82 (m, 2H), 3.12-2.99 (m, 2H), 3.80 (s, 3H), 4.16-4.04 (m, 1H), 4.54-4.42 (m, 2H), 6.92 (d, 1H), 7.18-7.10 (m, 1H), 7.33-7.21 (m, 2H), 7.97-7.92 (m, 1H), 8.04-7.98 (m, 1H), 8.65 (d, 1H), 9.03 (d, 1H), 10.62 (s, 1H); MS m/e MH+ 441.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:34]=[C:33]([NH2:35])[NH:32][N:31]=2)=[CH:26][CH:25]=1>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:35][C:33]3[NH:32][N:31]=[C:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[CH:34]=3)=[O:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Nc1cc(-c2ccc(F)cc2)n[nH]1
Product: O=C(Nc1cc(-c2ccc(F)cc2)n[nH]1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-(4-fluorophenyl)-1H-pyrazol-5-amine (43 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-8% MeOH in EtOAc. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-(4-fluorophenyl)-1H-pyrazol-5-yl)benzamide as an off white solid. Yield: 36 mg (31%). 1H-NMR: 11.11 (s, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.80 (dd, J=8.5, 5.5 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.5 Hz, 1H), 7.33-7.08 (m, 5H), 7.01 (br s, 1H), 3.83-3.79 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).
Reaction SMILES: [NH2-].[Na+].[CH2:3]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH3:4].Cl.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28].Cl>C1C=CC=CC=1>[CH2:3]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[O:24][CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])[CH3:4]
Reactant: CN(C)CCCl
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCN(C)C
Temperature: 25 °C

Procedure:
Stir a solution of 860 mg. of sodium amide in 15 ml. of benzene and add 3.0 g. of dl-13-ethyl-3-methoxygona-1,3,5(10)-trien-17β-ol in 15 ml. of benzene. Heat for 2 hours at 70°-83°. Cool to room temperature and add 1.58 g. of N,N-dimethylamino-2-chloroethane hydrochloride and reflux for 16 hours. Pour over ice and acidify reaction mixture with 2 N hydrochloric acid. Extract with ether and basify the aqueous layer with 15% sodium hydroxide. Isolate material with ether. Evaporate the ether to obtain dl-13-ethyl-17β-(2-dimethylaminoethoxy)-3-methoxygona-1,3,5(10)-triene.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH3:10][O:9][C:7]([C:6]1[C:5]([CH3:11])=[CH:4][S:3][C:2]=1[NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:8]
Reactant: COC(=O)c1c(C)csc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1scc(C)c1C(=O)OC)C(=O)OCC

Procedure:
Reaction of methyl 2-amino-4-methylthiophene-3-carboxylate with diethyl ethoxymethylenemalonate in a manner similar to that used in Reference Example 10 yields diethyl (3-methoxycarbonyl-4-methylthienyl)aminomethylenemalonate as crystals melting at 105.5°-106° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])[CH3:18]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 30 h
Yield: 85.5 %

Procedure:
1H-indole-2-carboxylic acid (1 g, 6.2 mmol) was dissolved in 20 mL of ethanol. To this thionyl chloride (5.86 g, 49.68 mmol) was added drop wise with stirring at 0° C and stirring was continued for 30 h at room temperature. Excess of SOCl2 was evaporated, water was added to the residue and the suspension was filtered to afford the title compound (1.0 g, yield: 85.5%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH3:15])[C:4]([NH:6][O:7]CC1C=CC=CC=1)=[O:5].[CH3:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=1)[C:18]([OH:20])=O>>[CH3:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=1)[C:18]([NH:2][C@H:3]([CH3:15])[C:4]([NH:6][OH:7])=[O:5])=[O:20]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: C[C@@H](N)C(=O)NOCc1ccccc1
Agent: Cl
Product: CC(C)Cc1ccc(C(C)C(=O)N[C@H](C)C(=O)NO)cc1

Procedure:
This compound was synthesized by coupling 2-amino-N-benzyloxy-(R)-propionamide HCl salt 42b with (R/S)-α-methyl-4-isobutylphenylacetic acid followed by hydrogenation using the procedures as described in Example 42. MS (ESI): (M−H)−=291.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:15]1([C:19]([CH3:21])=[O:20])[CH2:18][CH2:17][CH2:16]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:15]1([C:19](=[O:20])[CH2:21][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: CC(=O)C1CCC1
Reactant: Brc1ccc(OC2CCCCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C(Cc1ccc(OC2CCCCC2)cc1)C1CCC1
Temperature: 130 °C
Yield: 86.1 %

Procedure:
A stirred suspension of 1-bromo-4-cyclohexyloxy-benzene (Example 60, 4.18 mmol, 1.05 g), cyclobutylmethylketone (5.23 mmol, 0.57 mL), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.50 mmol, 0.31 g), tris(dibenzylideneacetone)dipalladium(0) (0.21 mmol, 0.19 g), and potassium t-butoxide (6.27 mmol, 0.70 g) was heated in a single mode microwave synthesizer to 130° C. for 1 h in a 10 mL microwave sealed tube. The reaction was cooled and partitioned in water (20 mL) and diethyl ether (50 mL). The mixture was filtered through fluted filter paper and the layers were separated. The aqueous layer was washed with diethyl ether (50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified on 2×40 g SiO2 cartridges stacked using a 0-20% ethyl acetate/hexanes gradient to give 1-cyclobutyl-2-(4-cyclohexyloxy-phenyl)-ethanone (0.98 g).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][O:9][C:8]=2[C:18]([O:20]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:23][NH2:24]>C(O)C>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][O:9][C:8]=2[C:18]([NH:23][NH2:24])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1occ(-c2ccccc2)c1-c1ccccc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1occ(-c2ccccc2)c1-c1ccccc1
Reaction time: 8 h

Procedure:
Ethanol (50 ml) was added to a mixture of methyl 3,4-diphenyl-2-furancarboxylate (14.00 g) and hydrazine monohydrate (7.33 ml), and heated at reflux while stirring overnight. After concentrating the reaction solution under reduced pressure and adding ethanol, the thus-precipitated crystals were filtered, thereby giving 13.80 g of the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])[CH:29]=1
Reactant: NCc1ccc(F)cc1N1CCCC1=O
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1CCCC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 1-(2-(aminomethyl)-5-fluorophenyl)pyrrolidin-2-one, derived from reduction of intermediate 111, 4-fluoro-2-(2-oxopyrrolidin-1-yl)benzonitrile. 1HNMR 400 MHz (MeOD) δ ppm: 7.44 (3H, m), 7.33 (3H, m), 7.11 (1H, dd, J=9.2, 3.0 Hz) 7.03 (1H, m), 5.21 (2H, s), 4.43 (2H, s), 4.08 (2H, t, J=5.0 Hz), 3.98 (2H, t, J=5.0 Hz), 3.85 (2H, t, J=7.1 Hz), 2.58 (2H, t, J=8.0 Hz), 2.23 (2H, m), 1.61 (6H, s). LCMS (M+H)+ m/z 521.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: OB(O)c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccncc4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and pyridine-4-boronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 1): tR=1.31 min; Mass spectrum (ESI+): m/z=380 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.COB(OC)OC.C(#N)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1COCCN1
Agent: COB(OC)OC
Solvent: O
Solvent: CC#N
Product: COc1c(N2CCOCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 1.48 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (5 mmol), 0.85 g of morpholine (10 mmol), 1.04 g of trimethoxyborane (10 mmol) and 7.5 ml of acetonitrile was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature, 20 ml of water was added therein, a pH was adjusted to 8 with 6N--HCl, and separated crystals were filtered and dried to obtain 1.30 g of the objective compound.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].CCN(C(C)C)C(C)C.[CH2:19](Cl)[O:20][CH3:21].[NH4+].[Cl-]>ClCCl>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH2:19][O:20][CH3:21]
Reactant: COCCl
Reactant: OCc1ccccc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1ccccc1I
Temperature: 23 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To stirring solution of 2-iodobenzyl alcohol (6.02 g, 25.72 mmol) in dichloromethane (40 mL) was added sequentially Hunig's base (6.8 mL, 38.51 mmol) followed by MOMCl (3.0 mL, 39.13 mmol), and stirred at 23° C. overnight. The reaction was treated with saturated NH4Cl (30 mL), stirred vigorously for several minutes, then the phases separated. The organic phase was extracted with dichloromethane (2×). The combined organics were dried (MgSO4), filtered and concentrated to an amber oil which was purified on Biotage Horizon (10-100% (7:3 hexane:EtOAc)/hexane, 40+M, SiO2) to afford the product (6.06 g) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (dd, J=7.83, 1.26 Hz, 1H), 7.45 (dd, J=7.70, 1.64 Hz, 1H), 7.35 (td, J=7.52, 1.14 Hz, 1H), 6.99 (td, J=7.58, 1.77 Hz, 1H), 4.76 (s, 2H), 4.59 (s, 2H), 3.43 (s, 3H).