Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6](/[CH:9]=[C:10]1\[CH2:11][N:12]([CH:17](C2CC2)[C:18]2[CH:19]([F:26])[C:20](=C=O)[CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:14][CH:15]\1[OH:16])([OH:8])=[O:7].Cl>C1C=CC=CC=1>[CH2:1]([O:8][C:6](/[CH:9]=[C:10]1\[CH2:11][N:12]([CH:17]([C:1]([CH:2]2[CH2:4][CH2:3]2)=[O:5])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:26])[CH2:13][CH2:14][CH:15]\1[OH:16])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C=C1C=CC=C(C(C2CC2)N2CCC(O)/C(=C/C(=O)O)C2)C1F
Reactant: CCCCO
Agent: Cl
Solvent: c1ccccc1
Product: CCCCOC(=O)/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1O
Reaction time: 2 h
Yield: 73.7 %

Procedure:
150 ml of 1-butanol were added to 3.19 g (9.58 mmol) of (E)-3-carboxymethylidene-1-(α-cyclopropyl-carbonyl-2-fluorobenzyl)-4-hydroxypiperidine. Hydrogen chloride gas was blown through the resulting mixture until the solution became acidic. After standing at room temperature for 2 hours, 100 ml of benzene were added and the mixture was subjected to azeotropic dehydration for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Toluene and an aqueous solution of sodium bicarbonate were added to the residue. The toluene layer thus separated was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by purification by chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=4/1), whereby 2.75 g (yield: 73.7%) of the tile compound were obtained as a pale yellow oil.
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:21])[CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[NH+:15]=3)Br)=[CH:10][C:5]=2[O:4][CH2:3]1.[C:22]([O-:25])(=[O:24])[CH3:23].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:21])[CH:12]([O:25][C:22](=[O:24])[CH3:23])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC(=O)[O-]
Reactant: Cc1cccc(C(Br)C(=O)c2ccc3c(c2)OCO3)[nH+]1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC(C(=O)c1ccc2c(c1)OCO2)c1cccc(C)n1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A solution of 2-(2-benzo[1,3]dioxol-5-yl-1-bromo-2-oxo-ethyl)-6-methyl-pyridinium bromide (150 mg, 0.36 mmol), and potassium acetate (70 mg, 0.72 mmol, 2 equiv) in dimethylformamide (2 mL) was heated to 60° C. for 1 hour. The resulting reaction mixture was cooled to ambient temperature, treated with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organics were washed with brine, dried with magnesium sulfate and concentrated in vacuo to provide acetic acid 2-benzo[1,3]dioxol-5-yl-1-(6-methyl-pyridin-2-yl)-2-oxo-ethyl ester (80 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[CH:29]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1cc(C(F)(F)F)no1
Product: O=C(NCc1cc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAS Registry No. 1018782-82-5) and 3-trifluoromethyl-isoxazol-5-methanamine (example BA) as starting materials; MS: 478.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CC#N>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:32]=[C:30]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:28][CH:27]=3)[N:31]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: CS(=O)(=O)c1ccc(NC(=N)N)cc1
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(S(C)(=O)=O)cc3)n2)s1

Procedure:
By condensation of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(4-methanesulfonyl-phenyl)-guanidine nitrate. Yellow solid. Anal. RP-HPLC: tR=16.6 min (0-60% MeCN, purity >97%). 1H-NMR (DMSO-d6) δ: 2.65 (s, 3H, CH3), 2.66 (s, 3H, CH3), 3.15 (s, 3H, CH3), 7.22 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.84 (d, 2H, J=9.0 Hz, Ph-H), 8.03 (d, 2H, J=9.0 Hz, Ph-H), 8.61 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 10.23 (sbr, 1H, NH). MS (ESI+) m/z 361.17 [M+H]+ (C16H16N4O2S2 requires 361.46).
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:5][CH2:4][CH2:3]1.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([C:19](=[O:24])N(OC)C)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1.[H-].C([Al+]CC(C)C)C(C)C.II>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([C:19]([CH:2]2[CH2:5][CH2:4][CH2:3]2)=[O:24])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: BrC1CCC1
Reactant: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: II
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)C2CCC2)C1
Temperature: 25 °C
Yield: 53 %

Procedure:
Add diisobutylaluminium hydride (1M in toluene, 0.790 mL, 0.790 mmol) to a stirred mixture of magnesium (0.960 g, 39.5 mmol) and iodine (0.100 g, 0.395 mmol) in THF (1 mL) under nitrogen. Add drop wise a solution of cyclobutyl bromide (8.00 g, 59.2 mmol) in THF (10 mL) and stir the reaction at 60° C. for 2 h whereby all the magnesium is consumed. Cool the mixture to room temperature and add drop wise a solution of (S)-3-(methoxy(methyl)carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (10.2 g, 39.5 mmol) in THF (50 mL). Stir the reaction mixture at room temperature for 2.5 h. Quench with 1 M aqueous citric acid, extract with EtOAc. Wash the organic layer with water and saturated aqueous NaCl, dry (Na2SO4), filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with EtOAc in hexanes (0-50% gradient) to obtain the title compound (5.30 g, 53%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C([NH:65][CH2:66][CH2:67][N:68]3[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:34]1([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH:25][C:4]2[N:3]=[C:2]([NH:65][CH2:66][CH2:67][N:68]3[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46). MS (ES+) m/e 636.42 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>CN(C)C=O.O1CCCC1>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([Cl:20])=[O:17])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
1 g (0.1 mole) of 2-acetoxy-6-naphthoic acid, 0.1 g of N,N-dimethylformamide and 185 g of tetrahydrofuran were fed into. 300 ml-glass container. To this mixture, 23.9 g of thionyl chloride was added dropwise at room temperature under stirring. Then, the reaction was heated to 50° C. and kept at this temperature for 30 minutes. From the resulting mixture, tetrahydrofuran and the excess thionyl chloride were distilled out using a rotary evaporator to give 24.9 g (0.1 mole) of 2-acetoxy-6-naphthoic acid chloride.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:7]=1)C.[OH-].[Li+]>CO.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:27])=[O:3])[CH:11]=[CH:10][CH:9]=2)=[C:14]([CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:15]=1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1

Procedure:
Hydrolysis of {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester with lithium hydroxide in MeOH and H2O provided the desired product.
Reaction SMILES: [P:1]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])([O:3]CC)=O.[CH2:12]([O:19][C:20]1[C:29]([CH2:30]Br)=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([O:32][CH3:33])=[N:27]2)=[N:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:10]([O:9][P:1]([CH2:30][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:32][CH3:33])[N:27]=2)[N:22]=[CH:21][C:20]=1[O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[O:6][CH2:7][CH3:8])[CH3:11]
Reactant: COc1ccc2ncc(OCc3ccccc3)c(CBr)c2n1
Reactant: CCOP(=O)(OCC)OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1c(OCc2ccccc2)cnc2ccc(OC)nc12)OCC
Yield: 77.2 %

Procedure:
Triethyl phosphate (960 μL, 5.60 mmol, 10.0 eq) is added at room temperature to a stirred solution of 7-benzyloxy-8-bromomethyl-2-methoxy-[1,5]naphthyridine (200 mg, 0.56 mmol, 1.0 eq) in toluene (1 mL) and the resulting mixture is heated under reflux for 6 hours. Solvent is then removed and the residue is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 1:1, v/v) to afford (3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-ylmethyl)-phosphonic acid diethyl ester as a yellow oil (180 mg, 79% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][N:13]([CH:16]3[CH2:18][CH2:17]3)[CH:14]=O)[CH:11]=1)[O:8][C:7]([CH3:20])([CH3:19])[CH2:6][C:5]2([CH3:22])[CH3:21].[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C(N(CC)CC)C.O1CCCC1.C(OCC)C.[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>[CH:16]1([N:13]([CH2:12][C:10]2[CH:11]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=[C:4]3[C:9]=2[O:8][C:7]([CH3:20])([CH3:19])[CH2:6][C:5]3([CH3:22])[CH3:21])[CH3:14])[CH2:18][CH2:17]1
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(CN(C=O)C3CC3)c2O1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C)C1CC1
Temperature: 70 °C

Procedure:
A solution of 6-bromo-8-[(cyclopropyl-formyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman (Intermediate 9, 1.5 g, 4.2 mmol) in triethyl amine (5 mL) and anhydrous tetrahydrofuran (10 mL) was treated with copper(I)iodide (0.32 g, 1.68 mmol) and sparged with argon for 5 minutes. Trimethylsilyl acetylene (2.5 mL, 17.6 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (0.737 g, 1.05 mmol). The resulting reaction mixture was heated at 70° C. for 17 h. It was then cooled to ambient temperature, diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) to afford the title compound as a brown oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].Cl.Cl.[CH2:23]([N:25]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1)[CH2:26][CH3:27])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].C>C(O)CC.Cl.Cl.C(N(CC1CCCCN1)CC)C.C(#N)C>[CH2:23]([N:25]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:26][CH3:27])[CH3:24]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCCO
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reaction time: 8 h
Yield: 65.1 %

Procedure:
A suspension of 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (276 g, 0.959 mol), and 2-[(diethylamino)methyl]piperidine dihydrochloride (244.95 g, 100.7 mol), of sodium carbonate (223.9 g, 2.112 mol) and acetonitrile (1.92 liters) are stirred for 6 hours at a reaction temperature of 70° C. After this time, the 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one has 95-97% reacted (TLC). The mixture is left to stand overnight at ambient temperature, then suction filtered. The contents of the filter are washed three times, each time with acetonitrile (60 ml). The dark colored filtrates are discarded. The remaining solid is stirred for a further 2 hours with water (1.5 liters), suction filtered again and washed with another water (300 ml) and finally dried at 40° C. in a circulating air drier. The crude product thus obtained (390 g) is transferred into a 10 liter flask, taken up in 1-propanol (5.14 liters) and, after the addition of 2-[(diethylamino)methyl]piperidine dihydrochloride (13.5 g, 0.0555 mol) and anhydrous sodium carbonate (11.8 g, 0.1113 mol), refluxed for 16 hours. After the addition of activated charcoal (39 g) the mixture is heated to boiling for a further 30 minutes and the boiling hot mixture is then forced through a SEITZ filter. Clarification is repeated twice more in the same way using activated charcoal (20 g). The filtrate is left to stand for 12 hours at ambient temperature, the precipitated crystals are suction filtered and washed twice, each time with 1-propanol (50 ml). The product is again stirred with cold 1-propanol (0.5 liters), suction filtered and again washed twice, each time with 1-propanol (50 ml). It is then dried in a circulating air drier at 40° C. and almost colorless crystals (263 g) are obtained, mp. 226°-227° C.
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].[CH2:26]([Mg]Br)[CH:27]([CH3:29])[CH3:28]>C1COCC1.C(Cl)Cl.O>[Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]([OH:25])[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)C[Mg]Br
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(O)c1c(Br)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.5 %

Procedure:
To a solution of 6-bromo-1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (400 mg, 0.92 mmol) in THF (5 mL) was added isobutylmagnesium bromide (0.92 mL, 0.92 mmol) dropwise. The reaction was stirred at RT for 5 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 6-bromo-5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (70 mg, 15.4% yield) as a solid. LCMS: MH+ 405 and TR=1.922 min.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12](OC)=[O:13])=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].C(OCC)(=O)C>C(O)C.[Cl-].[Na+].O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][OH:13])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC[C@H]1C(=O)OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC[C@H]1CO
Reaction time: 18 h
Yield: 44.3 %

Procedure:
To a solution of (2S)-1-allyloxycarbonyl-2-methoxycarbonylpyrrolidine (2.0 g) in ethanol (30 ml) was added sodium borohydride (1.06 g) at 20° C. and the resulting mixture was allowed to stir for 18 hours at 20°-25° C. The reaction mixture was taken up into a mixture of brine (100 ml) and ethyl acetate (100 ml). The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (50 ml) eluting with a mixture of dichloromethane and acetone (20:1) to give (2S)-1-allyloxycarbonyl-2-hydroxymethylpyrrolidine (769.2 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCCOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCc2ccccc2)CC1
Yield: 42.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.8 g) and 5-benzyloxypentyl bromide (2.08 g) were reacted and treated in the same manner as in Example 168 to give 0.82 g of 4-amino-N-((1-(5-benzyloxypentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([CH2:33][CH2:34]O)[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:45]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>CC#N.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([CH2:33][CH2:34][F:45])[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:26])([F:25])[F:27])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(CCO)nn2)cc1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(CCF)nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
To a solution of 2-(4-tert-Butylphenyl)-N-{(S)-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide (32.00 mg, 0.0650 mmol) in 0.5 ml of anhydrous CH3CN at RT was added diisopropylethylamine (0.0450 ml, 0.260 mmol), diisopropylethylamine dihydrogen fluoride complex (0.0180 ml, 0.0980 mmol), and perfluorobutanesulfonyl fluoride (0.0230 ml, 0.130 mmol). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by preparative HPLC (20-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 0.0171 g (53%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.245 (d, J=2.93 Hz, 1H), 7.569 (s, 1H), 7.527 (d, J=7.14 Hz, 1H), 7.369 (m, 2H), 7.270 (m, 1H), 7.225 (m, 2H), 6.336 (d, J=7.14 Hz, 1H), 4.800 (AB q, J=4.53 Hz, 1H), 4.682 (AB q, J=4.21 Hz, 1H), 4.617 (AB q, J=4.53 Hz, 1H), 4.550 (AB q, J=4.67 Hz, 1H), 4.378 (q, J=7.88 Hz, 2H), 3.623 (s, 2H), 3.086 (br s, 1H), 1.314 (s, 9H). ES-MS [M+1]+: 494.2.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=3)[N:23](S(C3C=CC(C)=CC=3)(=O)=O)[CH:22]=2)=[N:5][C:6]([NH:9][C:10]([CH3:20])([CH3:19])[C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12])=[N:7][CH:8]=1)#[N:2].O.O[Li].O>C1COCC1>[C:1]([C:3]1[C:4]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:30]([F:31])([F:33])[F:32])[CH:28]=3)[NH:23][CH:22]=2)=[N:5][C:6]([NH:9][C:10]([CH3:20])([CH3:19])[C:11]([NH:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[O:12])=[N:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)(C)C(=O)NCC(F)(F)F)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Nc1ncc(C#N)c(-c2c[nH]c3ncc(C(F)(F)F)cc23)n1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
2-(5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamide (29 mg, 0.046 mmol, 1.0 Eq.) was dissolved in THF (4 mL) and water (1 mL) and treated with LiOH.H2O (10 mg, 0.23 mmol, 15 eq) and allowed to stir at room temperature overnight. The reaction mixture was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with saturated aqueous NaHCO3 followed by brine, dried over MgSO4, filtered and the solvent evaporated. The residue was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/Petroleum Ether) to give the title compound as a white solid (13 mg, 60%). MS (ES+) m/e=472. 1H NMR (DMSO) 1.53 (6H, s), 1.58 (6H, s), 3.65-3.69 (2H, m), 3.75-3.79 (2H, m), 8.26-8.34 (2H, m), 8.45 (1H, s), 8.65-8.78 (6H, m), 8.96 (1H, s), 9.29 (1H, s), 13.05 (2H, brs) [1:1 Mixture of rotamers]
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[OH:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)CCc1ccnc(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1ccnc(O)c1

Procedure:
Ethyl β-(2-methoxy-4-pyridyl)propionate (89.1 g) and ethanolic HCl (200 ml) were stirred under reflux in ethanol (900 ml) for 48 hours. The reaction mixture was evaporated under reduced pressure to give an oily residue which was dissolved in water (300 ml). This solution was taken to pH9 with potassium carbonate solution and extracted into ethyl acetate (6×250 ml). The combined ethyl acetate extracts were washed with water, dried over MgSO4 and evaporated under reduced pressure to afford an oil which solidified to give white crystals of ethyl β-(2-hydroxy-4-pyridyl)propionate which were washed with petroleum ether (40°-60°) and dried in vacuo (59.58 g), m.p. 73°-76.5° C.