Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:13][CH:14]=1.C(N(CC)C(C)C)(C)C.I[CH2:47][C:48]([NH2:50])=[O:49].O>CN(C)C=O>[NH2:50][C:48](=[O:49])[CH2:47][N:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:3][C:2]=2[F:1])[CH:14]=[CH:13]/[C:12]/1=[N:15]/[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)cn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)/N=c2/ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a solution of benzyl {3-fluoro-4-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}carbamate (35.0 g, 69.0 mmol) in N,N-dimethylformamide (350 mL) were added N,N-diisopropylethylamine (15.6 mL, 89.6 mmol) and iodoacetamide (16.6 g, 89.6 mmol), and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate/tetrahydrofuran. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate and collected by filtration to give the title compound (28.0 g, 72%).
Reaction SMILES: Cl.[O:2]1CCO[CH:3]1[C:7]1[CH:8]=[C:9]([C:22]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([S:29][CH3:30])[N:23]=2)[C:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[N:11][CH:12]=1.C1COCC1>>[CH3:21][O:20][C:17]1[N:16]=[CH:15][C:14]([NH:13][C:10]2[C:9]([C:22]3[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([S:29][CH3:30])[N:23]=3)=[CH:8][C:7]([CH:3]=[O:2])=[CH:12][N:11]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(Nc2ncc(C3OCCO3)cc2-c2nc(C)nc(SC)n2)cn1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc(SC)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2 M Aqueous HCl (1.50 mL, 3.00 mmol) was added to a stirred solution of 5-(1,3-dioxolan-2-yl)-N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-2-amine (35 mg, 0.085 mmol) in THF (3.00 mL, 36.6 mmol) and the mixture was stirred at 25° C. for 2 h. A yellow precipitate gradually formed. The volatile solvents were minimized and the precipitate was collected and dried to give 6-(6-methoxypyridin-3-ylamino)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)nicotinaldehyde (27 mg, 0.073 mmol, 86% yield) as a yellow solid. LCMS (API-ES) m/z 369 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH2:19][OH:20])[C@H:12]([CH3:18])[CH2:13][C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CCOCC.C(=O)(O)[O-].[Na+].O.CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH:19]=[O:20])[C@H:12]([CH3:18])[CH2:13][C:14]([F:15])([F:16])[F:17])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: C[C@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: C[C@H](CC(F)(F)F)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88.8 %

Procedure:
A solution of 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide (prepared as in Example 1, 3.0 g, 8.53 mmol) in CH2Cl2 saturated with water (30 mL) was stirred under nitrogen at 0° C. Dess-Martin periodinane reagent (7.59 g, 17.90 mmol) was added in one portion. The resulting suspension was stirred at 25° C., monitoring the progress of reaction by TLC analysis (1:2 EtOAc/hexane). As the rate of conversion of the starting material slowed, additional 2 mL portions of CH2Cl2 saturated with water were added (three portions over 15 min). After 19 h at 25° C., the reaction was complete by TLC. The solution was diluted with Et2O (50 mL) and a solution of sodium thiosulfate, Na2S2O3 (93.83 mmol, 14.8 g, 11 eq) in 80% saturated aqueous sodium bicarbonate solution (50 mL) was added. The mixture was stirred rapidly for 10 min until both phases were clear. The layers were separated and the aqueous phase was extracted with ether (30 mL). The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to obtain a crude oil (2.67g). The crude product was purified by the Biotage Flash™ 60 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-formyl-2-methylbutyl]thiophene-2-sulfonamide as a colorless oil (2.65g, 88.93%).
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1OCCOCCOCCOCCOC1.[H-].[Na+].[Cl:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[C:33]([NH2:38])[N:32]=1>C1COCC1>[C:1]12([CH2:11][O:12][C:35]3[CH:36]=[C:31]([Cl:30])[N:32]=[C:33]([NH2:38])[N:34]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OCC23CC4CC(CC(C4)C2)C3)n1
Temperature: 25 °C

Procedure:
A solution of adamantan-1-yl-methanol (100 mg, 0.60 mmol) in THF (5 mL) was cooled 15 to 0° C. 15-Crown-5 ether (99 mg, 0.5 mmol) and NaH (60% in oil, 92 mg, 2.4 mmol) were added sequentially. The reaction was warmed to RT for 1 h, cooled to 0° C., and 4,6-dichloropyrimidin-2-ylamine (247 mg, 1.5 mmol) was added. The reaction was heated to 65° C. for 16 h, cooled to RT, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (EtOAc/heptane) provided 4-(adamantan-1-ylmethoxy)-6-chloro-pyrimidin-2-ylamine as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=[C:11]3[CH:10]=[CH:9]2)[CH2:3][CH2:2]1.[Cl:21]N1C(=O)CCC1=O>CC#N>[Cl:21][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([S:17]([NH2:20])(=[O:18])=[O:19])[CH:16]=2)[N:8]([CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:9]=1
Reactant: NS(=O)(=O)c1cnc2c(ccn2CC2CCOCC2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: NS(=O)(=O)c1cnc2c(c1)c(Cl)cn2CC1CCOCC1

Procedure:
A mixture of EXAMPLE 388C (0.15 g) and N-chlorosuccinimide (0.081 g) in CH3CN (8 mL) was heated at 90° C. for 16 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica to give the title compound.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br.[Br:6][CH:7]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]1=O>C(O)C>[BrH:6].[S:3]1[C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:1]=[C:2]1[NH2:4]
Reactant: O=C1CCNCCC1Br
Reactant: NC(N)=S
Agent: Br
Solvent: CCO
Product: Nc1nc2c(s1)CCNCC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
1.44 g thiourea was added to 4 g 5-bromo-azepan-4-one hydrobromide in 50 mL ethanol and stirred 3 h at 80° C. and over the weekend at RT. The precipitate was filtered and dried to yield 3.8 g of the product.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([O:24][CH2:25][C:26]#[N:27])[C:14]([C:28]3[CH:32]=[CH:31][O:30][CH:29]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:24][CH2:25][C:26]#[N:27])[C:14]([C:28]3[CH:32]=[CH:31][O:30][CH:29]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
t-Butyl 6-(benzenesulphonylmethyl)-2-(cyanomethoxy)-3-(furan-3-yl)benzoate (Intermediate 119, 0.043 g) was dissolved in DCM (2 ml) and water (1 drop) was added followed by trifluoroacetic acid (1 ml). The mixture was stirred at room temperature for 15 minutes then it was evaporated to dryness. The residue was redissolved in DCM and re-evaporated twice. The residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water containing 0.1% formic acid with a gradient of 40-55%. After evaporation, the residue was triturated with ether and the solid was collected by filtration to give 6-(benzenesulphonylmethyl)-2-(cyanomethoxy)-3-(furan-3-yl)benzoic acid (0.024 g) as a white solid.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[C:15]([CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[CH:14][N:13]=1.O>N1C=CC=CC=1>[NH2:18][C:16]1[C:15]([CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[CH:14][N:13]=[C:12]([NH:11][CH:1]=[O:3])[N:17]=1
Reactant: O=CO
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(Cc2cnc(NC=O)nc2N)cc(OC)c1OC
Yield: 75.5 %

Procedure:
2.64 g of formic acid/acetic acid anhydride are dripped, while cooling, into a suspension of 2.9 g of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine (trimethoprim) in 35 ml of pyridine and reacted at 50° to 60° C. for two hours. The reaction mixture is then poured into 400 ml of water and the precipitate is filtered off and recrystallized from a mixture of dimethylformamide and water. 2.4 g (75% of theory) of 4-amino-2-formamido-5-(3,4,5-trimethoxybenzyl)-pyrimidine of melting point 240° to 242° C. are obtained.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH:14]#[C:15][CH2:16][CH2:17][CH3:18]>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)#[C:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCC
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCC#Cc1nccs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.2 %

Procedure:
2-Bromo-1,3-thiazole (2.0 g, 12 mmol) and CuI (183 mg, 0.96 mmol) were combined in DME (30 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (8 mL, 60 mmol) and PdCl2(PPh3)2 (337 mg, 0.48 mmol) were added and 1-pentyne (979 mg, 14.4 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 6 h at which time GC/MS analysis indicated that the reaction was not complete. Additional 1-pentyne (3.0 mL, 29 mmol) was added and the reaction was heated to 35° C. under a condenser. After heating for 16 h, GC/MS analysis indicated that the reaction was complete. The mixture was filtered through Celite.™, and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane, 99:1, then 97:3 hexane:ethyl acetate to 2-(1-pentynyl)-1,3-thiazole (820 mg, 44% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) Δ7.76 (d, J=3.0 Hz, 1H), 7.28 (d, J=3.0 Hz, 1H), 2.47-2.42 (m, 2H), 1.68-1.60 (m, 2H), 1.08-0.99 (m, 3H). MS (ESI) 151.6 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:66]1[CH:78]=[CH:77][C:69]([O:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=2)=[CH:68][CH:67]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][C:66]1[CH:67]=[CH:68][C:69]([O:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=2)=[CH:77][CH:78]=1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: Brc1ccc(Oc2ccccn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1Nc1ccc(Oc2ccccn2)cc1
Temperature: 110 °C
Yield: 66 %

Procedure:
A mixture of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.843 mmol), palladium acetate (0.019 g, 0.084 mmol), xantphos (0.058 g, 0.101 mmol), cesium carbonate (0.767 g, 2.36 mmol) and 2-(4-Bromo-phenoxy)-pyridine (0.252 g, 1.01 mmol) in toluene (3 mL) was heated by microwave to 110° C. for 45 minutes. The reaction was diluted with ethyl acetate filtered through a Celite pad and purified by silica gel chromatography to give 5-(3,3-Dimethyl-but-1-ynyl)-3-[4-(pyridin-2-yloxy)-phenylamino]-thiophene-2-carboxylic acid methyl ester in 66% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:20][CH:21](OC)OC)S(C2C=CC(C)=CC=2)(=O)=O)[S:5][C:6]=1[CH3:7].Cl.[OH-].[Na+]>O1CCOCC1>[Br:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]=[CH:20][CH:21]=2)[S:5][C:6]=1[CH3:7]
Reactant: COC(CN(Cc1cc(Br)c(C)s1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1sc2cnccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
N-((4-bromo-5-methylthiophen-2-yl)methyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (20 g, 45 mmol) was dissolved in dioxane (70 ml) and treated with conc HCl (70 ml). The reaction was heated to reflux and stirring continued overnight. The reaction was cooled down to RT, then to 0° C. and rendered neutral with 2N NaOH. The mixture was extracted with ethyl acetate. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes to give 3-bromo-2-methylthieno[2,3-c]pyridine (6.2 g, 61% yield) as an yellow solid. MS (M+H)+ 229
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22]C(C)(C)C)=O)[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[F:27][CH:28]([F:32])C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]2[CH2:15][N:16]([C:20](=[O:22])[CH:28]([F:32])[F:27])[CH2:17][CH2:18][O:19]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(C(F)F)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
The (R)-tert-butyl 2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (3.00 g, 8.0 mmol) was dissolved in the solution of HCl in ethyl acetate (20 mL), and the mixture was stirred at room temperature for 2 hours until TLC indicated Boc group was removed. The volatile materials were removed in vacuo and the residues were dissolved in dichloromethane. To the solution, difluoroacetic acid (1.15 g, 12 mmol), HATU (7.60 g, 20.0 mmol) and DIPEA (6.20 g, 48.0 mmol) were added subsequently and stirred at room temperature overnight. The mixture was purified by C18 column chromatography to give the desired amide as yellow solid (2.1 g). MS (m/z): 358 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH:17]2[CH2:19][CH2:18]2)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(Br)cc1OC(F)(F)F
Yield: 67.4 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and cyclopropylamine (0.17 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclopropyl-2-(trifluoromethoxy)benzenesulfonamide (0.25 g, 68%) was provided after purification. MS (ESI) m/z 360. HPLC purity 100.0% at 210-370 nm, 9.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17](=[O:33])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[N:22]=[CH:21][N:20]=2)[CH2:12]1)=O)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([C@H:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:33])[CH:24]=1
Reactant: COc1ccccc1-c1cc(NC(=O)[C@H]2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1cc(NC(=O)[C@H]2CCCNC2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of (S)-3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXXIV) (7.0 g) in 50 ml of methanol was added 10% palladium hydroxide (1.5 g) under an atmosphere of nitrogen and the mixture was stirred at room temperature under an atmosphere of hydrogen for 8 hours. The reaction mixture was filtered through celite and the solvent was evaporated. The obtained product was taken in diethyl ether, stirred, filtered, washed with diethyl ether and dried under vacuum to obtain (S)-piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #17A) as a white solid (3.0 g, 62%), melting point 163-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: [H][H]
Reactant: COC(=O)CN(Cc1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CN(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Yield: 103.1 %

Procedure:
To a solution of 4.2 g of methyl 2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]acetate in 200 ml of ethanol-ethyl acetate (1:1) was added 0.42 g of 10% Pd on carbon (wet--50% H2O) and the mixture shaken in a Parr hydrogenator under 35 pounds per square inch of hydrogen for 4.5 hours at room temperature. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give 4.0 g of crystals. m.p. 100°-102° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][C:41]=1[F:42])[O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH:35][C:36](=[O:38])[CH3:37])=[N:34][C:29]2=[CH:28][CH:27]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:36]([NH:35][C:33]1[S:32][C:30]2[C:29]([N:34]=1)=[CH:28][CH:27]=[C:26]([O:25][C:24]1[CH:39]=[CH:40][C:41]([F:42])=[C:22]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]4([C:14]#[N:15])[CH2:13][CH2:12]4)[C:2]=3[Cl:1])[CH:23]=1)[N:31]=2)(=[O:38])[CH3:37]
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)nc2s1
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (0.33 g, 1.5 mmol) produced in Example C62(ii) in oxalyl chloride (1.5 mL) was added N,N-dimethylformamide (100 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1.5 mL) and tetrahydrofuran (1.5 mL), and the solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.33 g, 1.00 mmol) produced in Example C64(ii) in N,N-dimethylacetamide (3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (280 mg, 54%) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([CH:14]([CH2:20][S:21](Cl)(=[O:23])=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(Cl)Cl>[O:4]1[CH2:5][CH2:6][N:1]([S:21]([CH2:20][CH:14]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:23])=[O:22])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCOCC1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
6.6 g (75.8 mmol) of morpholine are added dropwise at -10° to a solution of 6.23 g (21.4 mmol) of ethyl 2-benzyl-3-chlorosulphonyl-propionate (EPA 0236734) in 150 ml of methylene chloride. The solution is stirred at -10° for 1 hour and at 0° for 1 hour and subsequently acidified with 1N hydrochloric acid. The organic phase is then extracted with 50 ml of water, dried over sodium sulphate and evaporated. For purification, the residue (7.64 g) is chromatographed on 300 g of silica gel using methylene chloride as the eluent. There are obtained 6.78 g of ethyl (RS)-α-[(morpholinosulphonyl)methyl]-hydrocinnamate as a colourless oil; MS: 341 (M)+. This is converted into (S)-α-[(morpholinosulphonyl)methyl]hydrocinnamic acid by enzymatic hydrolysis using α-chymotrypsin in an analogous manner to that described in Example 1(d).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13]([OH:16])[C:14]#[CH:15].C(NC(C)C)(C)C.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O.C(OCC)(=O)C>[OH:16][CH2:13][C:14]#[C:15][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: C#CCO
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: OCC#Cc1ccc2cc(O)ccc2c1

Procedure:
9.00 g (40.3 mmol) of 6-bromonaphthalen-2-ol, 3.5 g (62.4 mmol) of prop-2-yn-1-ol, 1.00 g (1.43 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.5 g (2.63 mmol) of copper(I) iodide and 10 ml of diisopropylamine are left to stir overnight at 80° C. in 60 ml of DMF. The batch is subsequently added to 200 ml of ethyl acetate, 400 ml of water are added, and the mixture is acidified using hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are evaporated in vacuo, and the residue is filtered through silica gel with toluene/ethyl acetate (2:1). Crystallisation of the crude product from toluene/heptane gives 6-(3-hydroxyprop-1-ynyl)naphthalen-2-ol as a colourless solid.