Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:5][CH2:4]1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>C1COCC1.O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[N:13]=[C:14]([NH:16][C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:29])[S:15][C:11]=1[C:9]([CH:6]1[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:8][CH2:7]1)=[O:10]
Reactant: O=C(O)c1ccncc1
Reactant: COC1CCC(C(=O)c2sc(N)nc2-c2ccco2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: COC1CCC(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
Compound 441 (579 mg, 1.89 mmol) was dissolved in THF (9.0 mL), and isonicotinic acid (931 mg, 7.57 mmol), EDC hydrochloride (1.45 g, 7.57 mmol) and 1-hydroxybenzotriazole monohydrate (1.16 g, 7.57 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 442 (664 mg, 85%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH2:21]Cl)[CH2:13][CH2:12]1)[CH3:3].[C:26]1(=[O:32])[NH:31][CH:29]([CH3:30])[CH2:28][CH2:27]1.[Li]CCCC.CCCCCC>C1COCC1>[CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:21][N:31]3[CH2:29][CH2:30][CH2:28][CH2:27][C:26]3=[O:32])[CH:23]=[CH:24][CH:25]=2)[CH2:13][CH2:12]1)[CH3:3]
Reactant: CC(C)Oc1ccccc1N1CCC(Cc2cccc(CCl)c2)CC1
Reactant: CC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccccc1N1CCC(Cc2cccc(CN3CCCCC3=O)c2)CC1

Procedure:
A solution of 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperidinyl]methyl]benzyl chloride (5.25 g, 0.0147 mol) in THF (90 mL) was added dropwise to a solution of γ-valerolactam (2.06 g, 0.02 mol) in THF (50 mL) which had been treated at 0° C. with 1.6M n-BuLi/hexane (12 mL, 1 mol equiv). The resulting solution was heated to reflux for 3 h, cooled, and quenched with MeOH (20 mL). The solution was evaporated to dryness to give a yellow oil. The residue was chromatographed on silica gel using 99:1/CHCl3 :MeOH as eluant to give 1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperidinyl]methyl]phenyl]methyl]-piperidin-2-one as a light yellow oil, 1.41 g (23%). MS (Cl CH4): m/e 421 (MH+). 1H NMR (CDCl3): δ1.3 (d, 6H), 1.8 (m, 4H), 2.0 (m, 2H), 2.4 (s, 1H), 2.9 (m, 3H), 3.2 (m, 2H), 3.6 (s, 1H), 3.7 (d, 1H), 4.6 (m, 3H), 5.0 (s, 1H), 6.9 (m, 2H), 7.1 (m, 2H), 7.3-7.6 (m, 4H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].C[Si]([C:19]#[N:20])(C)C.O>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:19]([CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[OH:2])#[N:20]
Reactant: COC(=O)c1cc(C=O)ccc1OC
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(C(O)C#N)ccc1OC
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a solution of methyl 5-formyl-2-methoxybenzoate (55.61 g) and zinc iodide (960 mg) in methylene chloride (560 ml) was added trimethylsilyl cyanide (48 ml) in an argon atmosphere under ice cooling and stirring, and the mixture was stirred for 6.5 hours as it was. The reaction mixture was poured into water and methylene chloride layer was separated. After washing with water, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved into 1,3-dioxolane (400 ml) and 2 N hydrochloric acid (200 ml) was added, which was allowed to stand for 1.5 hours at room temperature. The reaction liquor was poured into water and extracted with ethyl acetate. This was washed with water, brine and then dried over anhydrous sodium sulfate. This was concentrated to about 200 ml under reduced pressure and the crystals deposited were collected by filtration and dried to obtain 39.41 g (62%) of aimed compound as pale yellow crystals.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH:7]([CH3:9])[CH3:8])=[N:4][C:3]=1[CH3:10].[O:11]1CCC(C=O)[CH2:12]1>>[I:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:9][CH2:12][O:11][CH2:8]2)=[N:4][C:3]=1[CH3:10]
Reactant: O=CC1CCOC1
Reactant: Cc1nc(C(C)C)[nH]c1I
Product: Cc1nc(C2CCOC2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 159.2, except tetrahydrofuran-3-carbaldehyde was used in place of isobutyraldehyde.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]=[C:6]2[CH2:13][NH2:14]>CO.CC(O)=O.[Ni]>[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[CH2:13][NH2:14]
Reactant: NCC1=CCOc2ccc(F)cc21
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: NCC1CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 1-(6-fluoro-2H-chromen-4-yl)methanamine hydrochloride (1.36 g, 7.6 mmol) in MeOH (20 mL) and AcOH (10 mL) was added Raney Nickel (760 mg) at room temperature. The suspension was stirred at rt overnight under 50 psi of H2. The reaction mixture was filtered and concentrated. The residue was dissolved in DCM and washed with sat. NaHCO3, dried (Na2SO4), and concentrated to give 490 mg (36%) of the title compound as a green oil. [M+H] calc'd for C10H12FNO, 182. Found 182.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[CH:15]=[C:14]([NH2:16])[NH:13][N:12]=1.[C:17]([CH:20]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:21](OCC)=[O:22])(=O)[CH3:18]>CC1C=CC=CC=1C.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>[OH:22][C:21]1[N:13]2[N:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=4[CH:1]=3)[CH:15]=[C:14]2[N:16]=[C:17]([CH3:18])[C:20]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: Nc1cc(-c2ccc3c(c2)CCCC3)n[nH]1
Reactant: CCOC(=O)C(CC(=O)OC)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)Cc1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1O
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
A suspension of 3-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazol-5-amine (6 g, 28.1 mmol), 1-ethyl 4-methyl 2-acetylsuccinate (24.52 mL, 141 mmol) and Ts-OH.H2O (0.096 g, 0.506 mmol) in o-xylene (200 mL) was heated at 150° C. (oil bath temp) for 16 h. (Note: mixture became homogeneous and in about 15 min slowly yellow solid started crashing out of the reaction.) Then, the reaction mixture was cooled, diluted with hexanes (300 mL), filtered, washed with hexanes and dried to afford methyl 2-(7-hydroxy-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (8.4 g, 23.90 mmol, 85% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 7.78-7.62 (m, 2H), 7.15 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 3.64 (s, 3H), 3.58 (s, 2H), 2.82-2.77 (m, 4H), 2.33 (s, 3H), 1.78 (t, J=3.0 Hz, 4H). LCMS (M+H)=352.3.
Reaction SMILES: Cl[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1.[C-:15]#[N:16].[Na+]>CS(C)=O>[C:15]([CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1)#[N:16]
Reactant: COC(=O)c1cccc2c1CCC2Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc2c1CCC2C#N
Reaction time: 8 h

Procedure:
In 80 ml. of dimethylsulfoxide is dissolved 15 g. of methyl 1-chloroindan-4-carboxylate and the solution is stirred. Then, 5.3 g. of sodium cyanide is added, followed by stirring for 8 hours. Following the addition of 750 ml. of water, the reaction mixture is extracted with ether. The extract is washed with a saturated aqueous solution of sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (500 g. silica gel; eluant: chloroform). The described procedure gives methyl 1-cyanoindan-4-carboxylate as crystals melting at 76.5°-77.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.B(F)(F)F.[CH3:35]COCC>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:35])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][NH2:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN
Product: CNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 2.76 (d, J=4.55 Hz, 3H) 7.59 (dd, J=7.96, 1.39 Hz, 1H) 7.66 (s, 1H) 7.71 (d, J=7.83 Hz, 1H) 8.11 (br. s., 1H) 8.33 (d, J=6.32 Hz, 2H) 8.61 (d, J=4.55 Hz, 1H) 8.79-8.89 (m, 1H) 12.66-13.53 (m, 1H). MS m/z [M+H]+334.1.
Reaction SMILES: C1(C)C=CC=CC=1.C([N:10](CC)CC)C.[F:15][CH:16]1[CH2:23][C@@:22]2(C(O)=O)[C@H:18]([C:19](=[O:35])[N:20]([C@@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:28])[CH2:21]2)[CH2:17]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(OCC)(=O)C>[NH2:10][C@:22]12[CH2:23][CH:16]([F:15])[CH2:17][C@@H:18]1[C:19](=[O:35])[N:20]([C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[CH2:21]2
Reactant: CCN(CC)CC
Reactant: C[C@H](c1ccccc1)N1C[C@@]2(C(=O)O)CC(F)C[C@H]2C1=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1C[C@@]2(N)CC(F)C[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
Toluene (10 mL) and triethylamine (565 μL, 4.05 mmol) were added to (1R,5R)-7-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid (590 mg, 2.03 mmol). Then, diphenylphosphoryl azide (567 μL) was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the reaction solution was heated to reflux for one hour and blended with a mixture of ethyl acetate-saturated sodium bicarbonate water. The organic layer was dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was dissolved in dioxane (10 mL). 6N hydrochloric acid (10 mL) was added, and the mixture was heated with stirring at 70° C. for two hours. After washing with ether, the aqueous layer was made basic with a 10 M sodium hydroxide solution, followed by extraction with toluene five times. The extract was dried over magnesium sulfate and filtered, and then the solvent was evaporated under reduced pressure to give 476 mg (90%) of the title compound as a colorless oil. The product was used for the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)[CH2:22][C:23]1[CH:32]=C2C(C=CC=C2)=C[CH:24]=1.CC(C)=O>CCCCCC>[CH:22]([O:13][C:3]1[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[Br:1])=[C:23]([CH3:32])[CH3:24]
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1O
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(C)=COc1c(Br)cc(Br)cc1C(C)(C)C
Temperature: 23 °C
Reaction time: 56 h

Procedure:
In a 3000 mL 3-neck flask, equipped with Ar inlet and magnetic stirrer, is placed 2,4-dibromo-6-tert-butylphenol (70.0 g, 226 mmol), K2CO3 (37.6 g, 276 mmol, 1.2 eq), Nal (3.38 g, 22.6 mmol, 0.1 eq), p-methallyl chloride (33.9 mL, 339 mmol, 1.5 eq), and acetone (1500 mL). The reaction mixture is vigorously stirred at 23° C. for 56 hrs, and monitored by TLC analysis (pet. ether). The solids are removed by filtration, washed with acetone, and the filtrates rotoevaporated (bath temperature kept below 35° C.) to give an oil. The oil is dissolved in hexane (100 mL), and stirred with silica gel (80 g). The slurry is filtered through a pad of Celite, and eluted with additional hexane (6×100 mL). The filtrate is evaporated to give 2,4-dibromo-6-tert-butylphenyl isobutenyl ether as a yellow oil. The material is stored in the freezer and is used as soon as possible.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([C@H:11]2[CH2:13][C@H:12]2[C:14]([OH:16])=[O:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[O:20]=[C:18]1[O:10][C:9]([C@H:11]2[CH2:13][C@H:12]2[C:14]([OH:16])=[O:15])=[N:8][N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C(NNc1ccccc1)[C@H]1C[C@H]1C(=O)O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@@H]1c1nn(-c2ccccc2)c(=O)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.85 g (8.4 mmol) of cis-2-(N′-phenyl-hydrazinocarbonyl)-cyclopropanecarboxylic acid were dissolved in 20 ml of tetrahydrofuran and 0.823 g (2.8 mmol) of triphosgene were added. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue dissolved in acetonitrile/DMF. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a white solid. Yield: 980 mg.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[C:22]([O:26][C:27](=[O:35])[NH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:22]([O:26][C:27](=[O:35])[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)[CH2:31][CH2:30]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ncnc2sc(NC(=O)Oc3ccccc3)nc12
Solvent: CC#N
Product: COc1ncnc2sc(NC(=O)N3CCC(NC(=O)OC(C)(C)C)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-carbamic acid phenyl ester (6 g, 19.8 mmol) and piperidin-4-yl-carbamic acid tert-butyl ester (4.37 g, 21.8 mmol) in acetonitrile (400 mL) was heated to reflux for 1 h and was then stirred at 25° C. overnight. The resulting solid was collected by filtration, rinsed with acetonitrile and dried in vacuo to afford [1-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylcarbamoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (7.3 g, 90%) as a white solid; ES-HRMS m/e calcd for C17H24N6O4S (M+H)+ 409.1653, found 409.1653.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:31])[CH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:21]=2[CH2:20]1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:31])[CH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][C:28]([O:30][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])=[CH:29][C:21]=2[CH2:20]1)[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: CCOC(=O)CC1CCCc2ccc(O)cc2C1
Product: CCOC(=O)CC1CCCc2ccc(OCCCCNC(=O)OC(C)(C)C)cc2C1

Procedure:
The title compound is prepared according to the procedure of Example 19 except that (4-bromo-butyl)-carbamic acid tert-butyl ester is used in place of (3-bromo-propyl)-carbamic acid tert-butyl ester and (3-hydroxy-6,7,8,9-tetrahydro-5H-benzo-cyclohepten-6-yl)-acetic acid ethyl ester is used in place of (7-hydroxy-1,2,3,4-tetrahydro-napthalen-2-yl)-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]([NH2:20])=O)[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:26][CH3:27].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]#[N:20])[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc2cc(-c3ccsc3)n(Cc3cccc(C(N)=O)n3)c2cc1F
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2cc(-c3ccsc3)n(Cc3cccc(C#N)n3)c2cc1F
Reaction time: 0.83 h
Yield: 42.6 %

Procedure:
To a solution of 6-[6-fluoro-5-methoxy-2-(thiophen-3-yl)indol-1-ylmethyl]pyridine-2-carboxamide (165 mg) in N,N-dimethylformamide (2.1 mL) was added phosphoryl chloride (0.058 mL) under ice-cooling. This mixture was stirred for 50 minutes. The reaction mixture was quenched with a saturated aqueous sodium hydrogen carbonate solution (10 mL). Ethyl acetate and water were then added to the mixture to separate the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (67 mg). 1H-NMR (CDCl3) δ ppm: 3.94 (3H, s), 5.47 (2H, s), 6.62 (1H, s), 6.80 (1H, d, J=8.3 Hz), 6.87 (1H, d, J=11.3 Hz), 7.10-7.30 (3H, m), 7.35-7.45 (1H, m), 7.59 (1H, d, J=7.7 Hz), 7.65-7.75 (1H, m).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:22]4[C@@H:23]([CH:27]([CH3:29])[CH3:28])[CH2:24][O:25][CH2:26][C:21]4=[N:20][C:14]=3[C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.[Pd]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH:27]([CH3:28])[CH3:29])[N:22]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: CC(C)[C@H]1COCc2nc3c(N)nc4cc(OCc5ccccc5)ccc4c3n21
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H]1COCc2nc3c(N)nc4cc(O)ccc4c3n21
Reaction time: 8 h
Yield: 60.5 %

Procedure:
(11S)-3-(Benzyloxy)-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (800 mg, 2.05 mmol) was dissolved in 260 mL of ethanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 460 mg) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa) overnight. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with 1:1 CH2Cl2/ethanol and the combined filtrates were concentrated under reduced pressure to give an off-white solid. Chromatography (SiO2, 20-40% CMA/CHCl3) gave the desired product (370 mg) as an off-white solid, mp 210-215° C.
Reaction SMILES: [CH2:1]=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][SH:25].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][S:25][CH2:1][CH:2]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CN(C)CCS
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCNCC1
Product: CN(C)CCSCC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
The title compound of Step 10 (1.5 g, 5.95 mmol) was dissolved under argon in methanol (22 mL). To this solution was added 2-dimethylaminoethanethiol hydrochloride (843 mg, 5.95 mmol), piperidine (0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6 mmol), and the mixture was stirred at room temperature for 16 hours. The solvent was removed on a rotary evaporator and then the residue was purified by flash chromotography on silica gel, eluting with 20:1 CH2Cl2 :MeOH to give the pure title compound (0.5 g, 24% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C21H27NO2S+0.2H2O: C, 69.85; H, 7.65; N, 3.88. Found: C, 69.58; H, 7.60; N, 3.98.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[OH:22])=CC=1)([O-])=O.[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)=[O:27].CO>C1(C)C(C)=CC=CC=1>[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([NH:33][C:11](=[O:23])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[OH:22])[S:31][CH:32]=1)=[O:27]
Reactant: COc1cc(O)c(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: COC(=O)c1csc(N)n1
Solvent: CO
Solvent: Cc1ccccc1C
Product: COC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2O)n1
Temperature: 130 °C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
In 1 mL of xylene were suspended 200 mg of 2-hydroxy-4,5-dimethoxybenzoic acid 4-nitrophenyl ester and 119 mg of 2-amino-1,3-thiazole-4-carboxylic acid methyl ester in a stream of argon, which was then stirred at 130° C. for 12 hours. The reaction mixture was allowed to stand to cool, to which 1 mL of methanol was then added, followed by heating to reflux for one hour. The resultant reaction mixture was allowed to stand to cool, followed by collecting the precipitated crystal by filtration at 30° C. or lower before drying under reduced pressure to provide 180 mg of the title compound (5a) at a yield of 80%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[O:13]=[S:14]1(=[O:31])[CH2:19][CH2:18][N:17]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:16]2=[N:15]1.O>CS(C)=O>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:16]3=[N:15][S:14](=[O:31])(=[O:13])[CH2:19][CH2:18][N:17]3[CH:20]=[CH:21][CH:22]=2)=[CH:29][CH:28]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)COc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A mixture of potassium carbonate (300 mg), 1-iodo-2,2-dimethylpropane (430 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (200 mg) in DMSO (5 ml) was stirred at 150° C. for 1 hr. Water was added to give a precipitate. The precipitate was collected by filtration and washed with Et2O-water. The precipitate was crystallized from CH3CN-IPE to give the title compound (182 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21]I.[CH3:23][CH:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][C:24]([CH3:23])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: FC(F)(F)c1cccc(Sc2ccc(CCCI)c(Cl)c2)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Product: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)C(=O)OCC

Procedure:
2-Chloro-1-(3-iodopropyl)-4-(3-trifluoromethylphenylthio) benzene and diethyl 2-methylmalonate were reacted according to the same procedures as in Example 152 of WO 04026817 to obtain the target product as a colorless oil.