Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4](OC)(=[O:13])[C:5]1[CH:10]=[CH:9][C:8](OC)=[CH:7][CH:6]=1.O.Cl>CS(C)=O>[C:4]([CH2:2][C:1]#[N:3])(=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: N#CCC(=O)c1ccccc1
Temperature: 60 °C
Yield: 68.7 %

Procedure:
To a solution of acetonitrile (76 g) in DMSO (100 mL) was added methyl p-anisate (100 g) and the mixture was stirred with heating at 60° C. for one hour. The reaction mixture was allowed to cool, and cold water (500 mL) was added dropwise. The mixture was acidified with hydrochloric acid and the precipitated crystals were collected by filtration. The obtained crystals were extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give benzoylacetonitrile (60 g) as colorless crystals. A solution of 2-chlorobenzaldehyde (1.7 g), 3-aminopyrazole (1.0 g) and benzoylacetonitrile (1.8 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.63 g) as colorless crystals.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:52][OH:53]>CC(N(C)C)=O>[CH2:54]([C@H:51]([NH:50][C:26](=[O:28])[C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=2)=[CH:30][CH:29]=1)[CH2:52][OH:53])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccc(-c2ccncc2)cc1
Temperature: 100 °C

Procedure:
In a microwave vial containing 3 eq. of PS-DCC, 4-(pyridin-4-yl)benzoic acid (20 mg, 0.1 mmol) was added dissolved in DMA (1.0 ml). Then a solution of HOBT (14 mg, 0.1 mmol) dissolved in DMA (0.3 ml) was added followed by the addition of DIEA (36 μl, 0.2 mmol) dissolved in DMA (0.3 ml) and the addition of (S)-2-amino-3-phenylpropan-1-ol (17 mg, 0.11 mmol) dissolved in DMA (0.6 ml). The mixture was heated in the microwave to 100° C. for 600 seconds. The reaction was filtered through Si-Carbonate, 6 ml-1 g supplied by Silicycle chemical Division and transferred to 20 ml vials. The reaction was checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (TFA method). Product was characterized by 1H NMR, MS and LC/MS.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[CH3:18])=[CH:6]/[C@@H:7]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]2[C@@H:8]1[C@@H:9]([OH:17])[CH2:10][CH2:11]2)[CH3:2].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[CH3:18])=[CH:6]/[C@@H:7]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]2[C@@H:8]1[C:9](=[O:17])[CH2:10][CH2:11]2)[CH3:2]
Reactant: CCOC(=O)/C(C)=C/[C@@H]1CC[C@@H](C)[C@H]2CC[C@H](O)[C@@H]21
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)/C(C)=C/[C@@H]1CC[C@@H](C)[C@H]2CCC(=O)[C@@H]21

Procedure:
Compound (11a) is dissolved in an appropriate solvent, preferably in dimethylsulfoxide, and treated with a solution of IBX, preferably in dimethylsulfoxide. After stirring for up to several hours, water is added and the white precipitate is removed by filtration. The precipitate is washed, preferably with dimethylsulfoxide/water and a small amount of AcOEt. The filtrate is extracted, preferably with dichloromethane for several times, the combined organic phases are dried (using e.g. Na2SO4) and concentrated, preferably in vacuo. Chromatography purification (using e.g. a polar solvent gradient) is employed to yield compound (12a). The reaction of compound (11a) (A) and IBX (B) is preferably carried out with equivalents, on a molar basis, of A:B in the ratio of about 1:2.
Reaction SMILES: [NH2:1][CH:2]([CH2:38][CH3:39])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[Cl:40][CH2:41][C:42](Cl)=[O:43].CCN(C(C)C)C(C)C>>[Cl:40][CH2:41][C:42]([NH:1][CH:2]([C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])[CH2:38][CH3:39])=[O:43]
Reactant: CCC(N)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)CCl)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Yield: 44 %

Procedure:
2-Chloro-N-[1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-acetamide was obtained from treating[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester (0.580 g, 0.92 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.488 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl)piperidin-1-yl)-butan-1-one (0.049 g, 0.09 mmol, Chloro-acetyl chloride (0.010 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, 2-Chloro-N-[1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-acetamide (0.024 g, 44%) as an oil. ES-LCMS m/z 608 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ncc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of NaH (0.78 g) in anhydrous THF (17.5 ml) at −5° C. was added 4-bromo-1H-indazole (3.5 g) in anhydrous THF (35 ml). Benzenesulfonyl chloride (2.5 ml) in anhydrous THF (17.5 ml) was added dropwise over 10 mins. The reaction was stirred for 1 h at 0° C. then quenched with water. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and then evaporated to yield a solid residue that was triturated with methanol to give title compound, 5.18 g.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][N:5]2[C:6](=[O:15])[C:7]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=[C:4]2[CH:3]=1.[C:18]1([C:24]2[N:25]=[CH:26][NH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.[Cu]I>[C:18]1([C:24]2[N:25]=[CH:26][N:27]([C:2]3[CH:17]=[CH:16][N:5]4[C:6](=[O:15])[C:7]5[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=5[N:9]=[C:4]4[CH:3]=3)[CH:28]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: O=c1c2c(nc3cc(Br)ccn13)CCCCC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(nc3cc(-n4cnc(-c5ccccc5)c4)ccn13)CCCCC2
Yield: 38 %

Procedure:
A solution of 3-bromo-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one (50 mg, 0.17 mmol), 4-phenyl-1H-imidazole (37.4 mg, 0.26 mmol), CuI (8 mg, 0.04 mmol) and Cs2CO3 in DMF was stirred at 80° C. under nitrogen. The completion of the reaction was monitored by TLC. After the suspension was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL), the combined organic phases were concentrated to crude product and 23 mg desired product was obtained by column chromatography purification. MS (ESI): 357 (MH+); MS (ESI): 357 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.15-9.13 (d, J=7.83 Hz, 1H), 8.16 (s, 1H), 7.87-7.85 (d, J=7.38 Hz, 2H), 7.72 (s, 1H), 7.57-7.56 (d, J=2.19 Hz, 1H), 7.48-7.44 (t, J=7.35 Hz, 2H), 7.38-7.35 (d, J=7.08 Hz, 1H), 7.26 (m, 1H), 3.00-2.97 (m, 4H), 1.93-1.91 (m, 2H), 1.79-1.77 (m, 2H), 1.71-1.69 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([SH:14])=[N:11][C:10]=2[CH:15]=1)=[O:5])[CH3:2].[H-].[Na+].[C:18]([O:22][C:23]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29]Cl)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(OCC)(=O)C>CN(C=O)C>[C:18]([O:22][C:23]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29][S:14][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15][C:10]=2[N:11]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1ccc2oc(S)nc2c1
Reactant: CC(C)(C)OC(=O)CNCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2oc(SCCCNCC(=O)OC(C)(C)C)nc2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a solution of 5-ethoxycarbonyl-2-mercaptobenzoxazole (670 mg) in DMF was added 60% sodium hydride (126 mg) in oil under ice-cooling, and the mixture was stirred for 30 minutes. A solution of 3-tert-butoxycarbonylmethylaminopropyl chloride (623 mg) in DMF was added to the reaction mixture, and the mixture was stirred with heating at 60° C. for 18 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1 v/v) to give the title compound (594 mg, yield 50%).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[OH-:27].[K+]>CCO>[O:27]1[CH:18]=[CH:17][CH:16]=[C:25]1[CH:24]=[C:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH2:14][CH2:13][C:11]3[N:10]=[CH:9][NH:8][CH:12]=3)[CH:17]=2)[C:22]1=[O:26]
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C1C(=Cc2ccco2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 76 %

Procedure:
According to the method of Example 32, 4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylic acid tert-butyl ester (0.270 g, 0.75 mmol) was reacted with 2-furylaldehyde (0.095 mL, 1.14 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.190 g (76%) of the title compound as a foam which solidified on standing to give a dark red powder, mp 57-60° C.: CI-MS m/e 335 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[I:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:24][C:16]=2[I:15])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(I)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(I)c1

Procedure:
600 mg of methyl 2-amino-4-(methylsulfonyl)benzoate was added to a solution of 4 mL of H2O and 1 ml, of concentrated sulfuric acid. The solution was cooled to 0° C. and a solution of 206 mg of sodium nitrite in 1 mL of H2O was added slowly. The reaction mixture was stirred for 2 h and then a solution of 782 mg of potassium iodide in 2 mL of H2O was added dropwise at 0° C. The reaction was allowed to warm to room temperature and stirred for 5 h. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated Na2S2O3, dried (MgSO4) and evaporated. Purified by silica gel chromatography (5-50% ethyl acetate/hexane) to afford methyl 2-iodo-4-(methylsulfonyl)benzoate. 160 mg of methyl 2-iodo-4-(methylsulfonyl)benzoate was hydrolyzed via Procedure M to give 2-iodo-4-(methylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-iodo-4-(methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-iodo-4-(methylsulfonyl)benzamide. MS (Q1) 513.0 (M)+.
Reaction SMILES: [Cl:1][C:2]1[NH:3]C2[C:9]([CH:10]=1)=[CH:8][CH:7]=CN=2.[H-].[Na+].CI.[CH3:15][N:16]([CH:18]=O)[CH3:17]>>[Cl:1][C:2]1[N:3]=[C:15]2[N:16]([CH3:17])[CH:18]=[CH:7][C:8]2=[CH:9][CH:10]=1
Reactant: Clc1cc2cccnc2[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1ccc2ccc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6 chloro-7-aza indole (1.00 g, 6.55 mmol) in DMF (30 mL) at 0° C. was added sodium hydride (0.524 g, 13.11 mmol) and the mixture was stirred at 0° C. for 20 min. Methyl iodide (0.512 mL, 8.19 mmol) was added at 0° C. and the mixture was warmed to room temperature and stirred for 2 h. The reaction was stopped, quenched with water and extracted with ethyl acetate. The organic layer was washed with water. It was then dried over sodium sulfate and concentrated in vacuo to give 1.01 g of the desires product as a brown color oil. ESI-MS: m/z 167.0 (M+H)+
Reaction SMILES: [C:1](OC)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[H][H]>>[OH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CCCCCCCCCCCCCC(=O)OC
Reactant: [H][H]
Product: COC(=O)CCCCCCCCCCCCCCO
Reaction time: 8 h
Yield: 61 %

Procedure:
150 g (499 mmol) of dimethyl 1,15-pentadecandioate and 12 g (8.0% by weight per the diester) of the catalyst prepared in Preparative Example 1 were added to an autoclave and subjected to hydrogenation reaction at the hydrogen pressure of 20.0 Mpa at 250° C. After 8 hours, the degree of the conversion was 63% and the selectivity was 87%. The reaction was further continued, and after 10 hours, methyl 15-hydroxypentadecanoate was obtained in 61% yield. The results are shown in Table 2.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].C(OC([CH2:15][NH:16][CH2:17][C:18]([O:20][CH2:21][N:22]1[C:31]2[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=2[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:23]1)=[O:19])=O)(C)(C)C>C(OCC)(=O)C>[ClH:7].[CH3:15][NH:16][CH2:17][C:18]([O:20][CH2:21][N:22]1[C:31]2[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=2[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:23]1)=[O:19]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COC(=O)CNCC(=O)OC(C)(C)C)c12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COC(=O)CNC)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A 4N hydrogen chloride ethylacetate solution (1 ml) was added to an ethyl acetate solution (2 ml) of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl (tert-butoxycarbonylmethylamino)acetate (100 mg, 0.19 mmol) and stirred at room temperature for 3 hours. The deposited insoluble matter was collected by filtration, washed with acetone, and then dried, giving a white powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl methylaminoacetate hydrochloride (78. 3 mg, yield: 88%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH:21]=[CH2:22].CN(C)C=O>C(Cl)(Cl)Cl>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2)[CH:21]=[CH2:20]
Reactant: C=CCI
Reactant: Cc1cc(O)cc2ccc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C=CCOc1cc(C)c2[nH]c(=O)ccc2c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 54.8 %

Procedure:
A mixture of 6-hydroxy-8-methylcarbostyril (15.0 g, 85.7 mmol), potassium carbonate (23.4 g, 169.5 mmol), allyl iodide (15.6 g, 90.0 mmol), and N,N-dimethylformamide (120 ml) was stirred in a bath of 70° C. for 1.5 hours. The mixture was condensed, and the residue was dissolved in chloroform, followed by washing with water and 2N-NaOH. The washed material was dried and condensed. The resultant residue was recrystallized (chloroform--n-hexane) to obtain 10.11 g of 6-allyloxy-8-methylcarbostyril as pale brown prisms (54.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24](O)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]([CH3:26])([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)[CH3:25])[N:9]=2)=[CH:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CC1(C)CC=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(C)(C)c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCC(C)(C)CC3)n2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-amide (as prepared in Example 56, step (e)), N-methylpiperizine and thionyl chloride in DCM solvent according to the procedure in Example 14, step (e).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[C:9]([C:20]4[CH:25]=[CH:24][C:23]([S:26](=[O:35])(=[O:34])[NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][N:21]=4)[N:10]3[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:42](Br)[CH:43]=[CH2:44]>CN(C=O)C>[CH2:44]([N:27]([C@@H:28]([CH3:33])[C:29]([F:31])([F:30])[F:32])[S:26]([C:23]1[CH:24]=[CH:25][C:20]([C:9]2[N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:12]=3)=[N:21][CH:22]=1)(=[O:35])=[O:34])[CH:43]=[CH2:42]
Reactant: C[C@H](NS(=O)(=O)c1ccc(-c2cc3ccc(C4CC4)cc3n2C(=O)OC(C)(C)C)nc1)C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN([C@@H](C)C(F)(F)F)S(=O)(=O)c1ccc(-c2cc3ccc(C4CC4)cc3n2C(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 6-cyclopropyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-1-carboxylate (503 mg, 0.99 mmol) and K2CO3 (276 mg, 2 mmol) in DMF (5 mL) was added allyl bromide (0.11 mL, 1.30 mmol). The mixture was stirred at room temperature for 2 hrs, and quenched with water (60 mL). The mixture was extracted with CH2Cl2 (3×20 mL). The solvent was then evaporated and (S)-tert-butyl 2-(5-(N-allyl-N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-6-cyclopropyl-1H-indole-1-carboxylate was obtained as a light yellow oil (500 mg, 92% yield). MS m/z 550.3 M+H+. This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][CH:10]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][CH:10]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cc(Cn3ncc(N)n3)cs2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)cs1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-3-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([CH:16]2[CH2:17][CH2:18][N:19]([C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:20][CH2:21]2)=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1Oc1ccc(Cl)cc1)C1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To an ice cooled solution of piperidine-4-carboxylic acid [2-(4-chlorophenoxy)phenyl]amide (AMR01033, 73 mg, 0.22 mmol) in dry DCM (6 mL) were added pyridine (0.036 mL, 0.44 mmol) and benzoyl chloride (0.038 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until TLC showed consumption of starting material (1 h), and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane to EtOAc gradient as eluent gave 1-benzoylpiperidine-4-carboxylic acid [2-(4-chlorophenoxy)phenyl]amide (80 mg, 83%) as a white solid, mp 158-160° C. Rf: 0.48 (EtOAc) LC/MS (APCI) tr=1.05 min, m/z 437.33 (45), 435.38 (M++H, 100) HPLC tr=2.551 min (98.36%) 1H NMR (270 MHz, CDCl3) δ 1.82 (4H, m, 2CH2), 2.51 (1H, tt, CH), 2.98 (2H, n, CH2), 3.85 (1H, m, ½CH2), 4.71 (1H, m, ½CH2), 6.82 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.93 (2H, AA′BB′, ArH), 7.02 (1H, td, ArH), 7.13 (1H, td, ArH), 7.31 (1H, AA′BB′, ArH), 7.39 (5H, s, ArH,), 7.70 (1H, br s, NH) and 8.39 (1H, dd, J=8.2, 1.5 Hz, ArH). Anal. Calcd. for C25H23ClN2O3: C, 69.04; H, 5.33; N, 6.44. Found: C, 68.9; H, 5.33; N, 6.37%.
Reaction SMILES: C(Cl)(Cl)Cl.[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]4[C:41]5[C:36](=[C:37]([NH2:42])[CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][C:33]4=[O:43])[CH2:26][CH2:25]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45]>C(N(CC)CC)C>[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]4[C:41]5[C:36](=[C:37]([NH:42][C:47]([NH:46][CH2:44][CH3:45])=[O:48])[CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][C:33]4=[O:43])[CH2:26][CH2:25]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
To 2 mL of a chloroform solution containing 80 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 45 mg of triethylamine and 31 mg of ethyl isocyanate were added, and stirred at room temperature for 3 days. The reaction mixture was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate: methanol=10:1], to give 60 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(3-ethylureido)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.