Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][C:7](Cl)=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:18]=2)=[CH:13][C:12]=1[O:33][CH3:34]>N1C=CC=CC=1.ClCCl>[NH2:26][C:24]1[C:25]2[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:7](=[O:8])[O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[C:12]([O:33][CH3:34])[CH:13]=3)=[CH:18][N:19]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCC(C)(C)C
Reaction time: 0.17 h

Procedure:
Neopentylchloroformate(13 uL, 0.110 mmol) was added dropwise to a stirring solution of 5-(4-amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (25 mg, 0.074 mmol) in pyridine (0.7 ml) and dichloromethane (0.7 ml) under nitrogen at 0° C. After 10 minutes, the ice water bath was removed and the resulting mixture was stirred for 4 hours. The solvent was evaporated and the residue was purified by preparative TLC using dichloromethane/methanol (95:5) as the mobile phase to give neopentyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate. 1H NMR (CDCl3) δ 1.00 (s, 3H), 2.07 (m, 4H), 3.65 (m, 2H), 3.91 (s, 2H), 3.94 (s, 3H), 4.13 (m, 2H), 4.97 (m, 1H), 5.18 (s, 2H), 6.97 (s, 1H), 7.03 (s, 1H), 7.07 (d, J=8 Hz, 1H), 7.25 (s, 1H), 8.19 (br. s, J=8 Hz, 1H). 8.33 (s, 1H). LC/MS (MH+=454).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>O1CCCC1>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:31])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: C#CCN1CCCc2ccc(O)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccccc3Br)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-bromophenyl isocyanate (396 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 36 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to afford 10c as solid. Yield: 540 mg, 65.61%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][CH2:35][CH2:36][CH2:37][OH:38])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][CH2:35][CH2:36][CH2:37][OH:38])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(NCCCO)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)NCCCO)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-(3-hydroxypropyl)benzenesulfonamide. MS (ESI): mass calcd. for C19H19FN4O3S, 402.12; m/z found, 403.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (d, J=1.2, 1H), 8.30 (s, 1H), 8.08-8.03 (m, 1H), 8.01-7.96 (m, 1H), 7.70-7.63 (m, 1H), 7.62-7.56 (m, 1H), 7.42-7.32 (m, 1H), 7.36-7.28 (m, 2H), 3.51 (t, J=6.2, 2H), 2.88 (t, J=7.0, 2H), 1.65-1.54 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:20])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)=[CH:5]/[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+]>C(O)C>[CH:7]1([CH2:6]/[CH:5]=[C:4](\[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)/[C:3]([OH:20])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)/C(=C/CC1CCCC1)c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C(=C/CC1CCCC1)c1ccc(F)c(F)c1
Temperature: 40 °C
Yield: 85.6 %

Procedure:
A solution of (E)-4-cyclopentyl-2-(3,4-difluoro-phenyl)-but-2-enoic acid methyl ester (0.80 g, 2.85 mmol) in ethanol (14 mL) was treated with a 1N aqueous sodium hydroxide solution (6 mL). The solution was heated at 40° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (30 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×80 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-4-cyclopentyl-2-(3,4-difluoro-phenyl)-but-2-enoic acid (0.65 g, 86%) as a colorless oil: EI-HRMS m/e calcd for C15H16F2O2 (M+H)+ 267.1196, found 267.1195.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:3][CH2:4][OH:5].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>CCOCC>[C:16]1(=[O:21])[N:1]([CH:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[CH2:3][CH2:4][OH:5])[C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12
Reactant: COc1ccc(C(N)CCO)cc1OC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCOCC
Product: COc1ccc(C(CCO)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
A mixture of 3-amino-3-(3',4'-dimethoxyphenyl)-propan-1-ol (1.11 grams, 5 mmol) and phthalic anhydride (0.74 grams, 5 mmol) were melted together and stirred for 5 minutes. After cooling, a green/yellow glassy semi solid formed which was stirred in ether to afford 1.62 g (95%) of crude product as a white solid. The crude product was purified by flash chromatography (silica gel, 40% ethyl acetate/methylene chloride) to afford 1.25 grams (73%) of product as a white solid. 1H NMR (CDCl3)δ7.85-7.63 (m, 4H), 7.18-7.07 (m , 2H), 6.86-6.76 (m, 1H), 5.62-5.49(m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.79-3.63 (m, 2H), 2.89-2.71 (m, 1H), 2.64-2.47 (m, 1H), 1.87-1.73 (br m, 1H). 13C NMR (CDCl3)δ168.5, 148.8, 148.6, 133.9, 131.8, 131.7, 123.2, 120.7, 111.6, 110.8, 59.8, 55.0, 55.8, 51.4, 33.9. Anal. Calcd. for C19 H19NO5. Theoretical: C, 66.85; H, 5.61 ;N, 4.10. Found: C, 66.70; H, 5.60; N, 4.06. HPLC 100%.
Reaction SMILES: Br[C:2]1[C:3]([CH:15]=[O:16])=[N:4][N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.CC1(C)C(C)(C)OB([CH:25]=[CH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:26]=[CH:25][C:2]2[C:3]([CH:15]=[O:16])=[N:4][N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=2)[CH:28]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c(C=O)n1
Reactant: CC1(C)OB(C=Cc2cccnc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C=Cc2cccnc2)c(C=O)n1
Temperature: 120 °C

Procedure:
After the solution of 4-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-3-carbaldehyde Compound 3a (570 mg, 1.87 mmol) and 3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-vinyl]-pyridine Compound 3c (863 mg, 3.74 mmol) in dioxane (35 mL) was degassed by evacuating and purging with nitrogen. [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex (Pd(dppf)2Cl2) (273 mg, 0.374 mmol) and sodium carbonate in water (3.74 mL, 2M) were added to the reaction mixture. The resultant suspension was purged again with nitrogen and heated at 120° C. for 30 min in a microwave reactor. After the solvent was removed in vacuo, the residue was dissolved in methanol and loaded to silica gel directly. The crude compound was eluted with a gradient of 4:1 to 2:1 hexane/ethyl acetate by flush chromatography to yield 4-(2-pyridin-3-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-3-carbaldehyde Compound 3d (385.6 mg, 0.624 mmol, 72% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.26 (s, 1H), 8.75 (s, 1H), 8.55 (d, 1H), 7.91 (m, 3H), 7.54 (d, 1H), 7.50 (t, 2H), 7.34 (dd, 2H), 7.11 (d, 1H), 5.82 (s, 2H), 3.62 (t, 2H), 0.94 (t, 2H), 0 (s, 9H); MS (ESI) m/z: 330.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][C:26]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:28][N:27]=2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)nc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
To a solution of 3-ethynyl-pyridin-2,6-diamine (230 mg, 1.73 mmol) described in Manufacturing Example 13-1-3 in anhydrous tetrahydrofuran (20 mL) was added (2-benzyloxy-pyridin-5-yl)-acetohydroximoyl chloride (1.00 g, 3.61 mmol) described in Manufacturing Example 12-1-5 under nitrogen atmosphere at room temperature. Triethylamine (965 μL, 6.92 mmol) was added dropwise to the mixture and stirred for 1.5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (470 mg, 73%).
Reaction SMILES: [Na].C(O[CH:7]=[CH:8][C:9](=O)[C:10]([F:16])([F:15])[C:11]([Cl:14])([F:13])[F:12])CCC.[C:18]([NH2:24])(=[O:23])[CH2:19][C:20]([NH2:22])=[O:21]>CO>[Cl:14][C:11]([F:12])([F:13])[C:10]([C:9]1[NH:22][C:20](=[O:21])[C:19]([C:18]([NH2:24])=[O:23])=[CH:7][CH:8]=1)([F:15])[F:16]
Reactant: NC(=O)CC(N)=O
Reactant: CCCCOC=CC(=O)C(F)(F)C(F)(F)Cl
Agent: [Na]
Solvent: CO
Product: NC(=O)c1ccc(C(F)(F)C(F)(F)Cl)[nH]c1=O

Procedure:
0.53 g (22.8 mmol) of sodium were dissolved in 50 ml of methanol, 5.0 g (19.0 mmol) of 1-butoxy-5-chloro-4,4,5,5-tetrafluoropent-1-en-3-one and 2.0 g (19.0 mmol) of malonamide were then added and the mixture was heated under reflux for 6 h. The mixture was concentrated, and 1N hydrochloric acid was then added. The resulting precipitate was filtered off with suction and dried. This gave 3.8 g (73% of theory) of a brownish powder.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:21][C@H:22]([CH2:26][CH3:27])[C:23]([NH2:25])=[O:24])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:25][C:23](=[O:24])[C@H:22]([NH:21][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[C:3]([C:1]([NH2:2])=[O:34])=[N:4][CH:5]=1)[CH2:26][CH3:27]
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc3c(c2)CCC(=O)N3)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc3c(c2)CCC(=O)N3)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound (R)-2-(5-cyano-6-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrazin-2-ylamino)butanamide (72 mg, 0.197 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (48 mg). MS 384.3 (M+H); UV 207.8, 308.9 nm; t 0.465 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:10]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[CH3:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:10]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[CH3:18])(=[O:21])[CH3:20]
Reactant: CCCCCc1ccc2nc(C)c(C)c(O)c2c1
Reactant: CC(=O)OC(C)=O
Product: CCCCCc1ccc2nc(C)c(C)c(OC(C)=O)c2c1
Yield: 74 %

Procedure:
100 Milligrams of 4-hydroxy-2,3-dimethyl-6-n-pentyl-quinoline (Compound No. 97) was stirred in 2 ml of acetic anhydride at 120° C. for 4 hours. After the solvent was evaporated, 20 ml of ethyl acetate was added and the reaction mixture was washed with an aqueous saturated sodium hydrogencarbonate solution and a saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-100) eluting with n-hexane/ethyl acetate (5:1) to obtain 87.4 mg of 4-acetoxy-2,3-dimethyl-6-n-pentyl-quinoline (yield 74%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].Cl.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:37]3[CH2:38][CH2:39][C@@H:35]([F:34])[CH2:36]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCCl)c2n1
Reactant: F[C@@H]1CCNC1
Agent: Cl
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(CCCCCCN3CC[C@@H](F)C3)c2n1

Procedure:
Prepared similarly to Intermediate 24 from 5-butyl-3-(6-chlorohex-1-yn-1-yl)-N-(3,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine and (R)-3-fluoropyrrolidine hydrochloride
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[S:9])[C:5]([CH3:8])=[CH:6]O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>CO.O.Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:6]=[C:5]([CH3:8])[C:4]([O:3][CH3:2])=[S:9]
Reactant: COC(=S)C(C)=CO
Reactant: COc1ccc(N)cc1Cl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=S)C(C)=CNc1ccc(OC)c(Cl)c1

Procedure:
Sodium (7.65 g.) was dissolved in anhydrous methanol (450 ml.) and the solution evaporated to dryness. The resulting sodium methoxide was suspended in anhydrous diethyl ether (300 ml.). The suspension was stirred at 0° and methyl methylthioacetate (40 g.) was added dropwise. The mixture was stirred at 0° for 1 hour and then treated dropwise with methyl formate (21 g.). The mixture was stirred at 0° for 1 hour and then stirred overnight at room temperature. The resulting suspension of solid was extracted with water (300 ml.) and the aqueous extract adjusted to 333 ml. with water. This aqueous extract containing methyl-3-hydroxy-2-methylthioacrylate, sodium salt (0.33 mole) was added to a stirred solution of 3-chloro-4-methoxyaniline (52 g.) in a mixture of water (800 ml.) and 11.6 N hydrochloric acid (33 ml.) at 0°. The mixture was stirred for 30 minutes and the product collected by filtration to give the novel intermediate compound methyl 3-(3-chloro-4-methoxyanilino)-2-methylthioacrylate, m.p. 110°-112°. This acrylate (77.6 g.) was added to diphenyl ether (200 ml.) stirred at 250° under nitrogen. After stirring at 250° for 15 minutes the mixture was cooled. The resulting precipitate was collected by filtration to give the novel intermediate compound 7-chloro-6-methoxy-3-methylthio-4-quinolone, m.p. 288°-290° (dec.) Examination by thin layer chromatography showed the presence of a minor amount of the corresponding 5-chloro isomer.
Reaction SMILES: C(OC([N:6]=[S@:7]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C@H:26]([CH3:29])[CH2:27][OH:28])[C:22]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)=[CH:21][N:20]=2)=[CH:14][CH:13]=1)([CH:9]1[CH2:11][CH2:10]1)=[O:8])=O)C.CC[O-].[Na+]>>[OH:28][CH2:27][C@H:26]([NH:25][C:23]1[C:22]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:21][N:20]=[C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([S@:7]([CH:9]3[CH2:11][CH2:10]3)(=[NH:6])=[O:8])=[CH:13][CH:14]=2)[N:24]=1)[CH3:29]
Reactant: CCOC(=O)N=[S@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1)C1CC1
Agent: CC[O-]
Agent: [Na+]
Product: C[C@H](CO)Nc1nc(Nc2ccc([S@](=N)(=O)C3CC3)cc2)ncc1-c1cccs1
Yield: 82 %

Procedure:
In the reaction of (R)—N-(ethoxycarbonyl)-S-(4-{[4-{[(R)-2-hydroxy-1-methyl-ethyl]amino}-5-(2-thienyl)pyrimidine-2-yl]amino}phenyl)-S-cyclopropyl-sulfoximide with sodium ethylate according to procedure 14, the desired product is obtained in 82% yield after chromatographic purification (silica gel, dichloromethane/ethanol (0-10% ethanol)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[NH2:30][C:31]1([CH3:35])[CH2:34][S:33][CH2:32]1.O>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7](=[O:27])[NH:30][C:31]2([CH3:35])[CH2:34][S:33][CH2:32]2)[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: CC1(N)CSC1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NC2(C)CSC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 50 °C
Yield: 40 %

Procedure:
To a solution of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (1.13 g, 2.56 mmol) (prepared according to WO 02/48115, example 2D) in tetrahydrofuran (15 ml) is added 3-amino-3-methyl-thietane (the product of step 3) (0.66 g, 6.40 mmol), and the mixture is heated for 48 hours at 50° C., then to reflux for 12 hours. The cooled reaction mixture is poured into water, extracted with ethyl acetate, the combined organic layers washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product is purified by flash chromatography (ethyl acetate/hexane 1:2) to afford 560 mg (40%) of the title compound as a white solid, m.p. 238-241° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])[CH:5]=[CH:4][C:3]=1[CH:25]([CH3:35])[CH2:26][NH:27]C(=O)OC(C)(C)C.[ClH:36]>CCOCC>[ClH:36].[NH2:27][CH2:26][CH:25]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])=[CH:7][C:2]=1[F:1])[CH3:35]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CN)c(F)c1
Yield: 91 %

Procedure:
Following General Procedure D1, tert-butyl 2-(2-fluoro-4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (200 mg, 0.40 mmol) was reacted with HCl in ether (20 mL) to afford the desired product (145 mg, 91%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.06 (s, 3H), 7.74 (dd, J=14.6, 5.4 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.30 (s, 1H), 7.16-7.02 (m, 2H), 5.87 (dd, J=43.2, 5.4 Hz, 1H), 3.70 (s, 3H), 3.51-3.40 (m, 1H), 3.26-3.07 (m, 2H), 2.59 (s, 3H), 1.39 (t, J=7.6 Hz, 3H); ESI MS m/z 397 [C22H21FN2O2S+H]+; HPLC 98.8% (AUC), tR=11.60 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:30][N:31]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:36][C:33]4[CH:34]=[N:35][N:31]([CH3:30])[CH:32]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: Cn1cc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (388 mg) and 1-methylpyrazole-4-carboxyaldehyde (540 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (519 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 1 day. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:3) to give methyl 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (321 mg) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=2)[N:3]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1cccc(-c2cc(Cl)nc(Cl)n2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(-c2cc(N3CCOCC3)nc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 38540 %

Procedure:
2,4-dichloro-6-(3-(methylsulfonyl)phenyl)pyrimidine (220 mg, 0.72 mmol, 1 eq) was dissolved in EtOH (5 mL) and DIEA was added (0.31 mL, 2.2 mmol, 3 eq). The reaction mixture was cooled to 0° C. and morpholine (94 mg, 1.1 μmol, 1.6 eq) was added. The reaction mixture was stirred at room temperature for 3 days. The ethanol was concentrated under reduced pressure and the residue was partitioned between EtOAc and sat. aq. NaHCO3. The organic layer was separated, washed with water and dried (Na2SO4). The residue was purified by column chromatography on silica gel (3% EtOAc/DCM to 40% EtOAc/DCM) to obtained the desired product (150 mg, 58%). LCMS (m/z): 302.8 (MH+), Rt: 1.51 min.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH2:11][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3[nH]ccc3c2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(-c2ccc3c(c2)CCN3)cc1
Yield: 93.1 %

Procedure:
5-Phenylindole (D29) (0.85 g, 4.4 mmoles) was dissolved in glacial acetic acid (20 ml) and treated with sodium cyanoborohydride (1.34 g, 22 mmoles) at ambient temperature for 2 hrs. Water (100 ml) was added and the mixture basified with sodium hydroxide. Extraction with dichloromethane gave the title compound (D30) (0.8 g, 93%).