Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][C:14]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:15][CH2:16][C:17](OC)=[O:18].O>S(=O)(=O)(O)O>[CH3:13][C:14]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:15][CH2:16][C:17]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])=[O:18]
Reactant: COC(=O)CC=C(C)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=CCC(=O)OC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.65 g (3.7 mmol) of ascorbic acid was dissolved in concentrated sulfuric acid (18 mL). After addition of 1.0 g (3.7 mmol) of methyl 4,8,12-trimethyltridec-3-enoate, the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into iced water, and extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.[C:23]1([C:29]2[S:33][N:32]=[C:31]([CH2:34]O)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.CCOC(C)=O>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:34][C:31]5[N:30]=[C:29]([C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)[S:33][N:32]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reactant: OCc1nsc(-c2ccccc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OCc2nsc(-c3ccccc3)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 8.25 mg, 0.026 mmol) and (5-phenyl-1,2,4-thiadiazol-3-yl)methanol (Example 7B, 5 mg, 0.025 mmol) were put in a flask and this was flushed with N2. Dry THF (4 mL) was added and to this resulting suspension was added tri-n-butylphosphine (0.017 mL, 0.065 mmol) and a solution of 1,1′-(azodicarbonyl)dipiperidine (16.57 mg, 0.065 mmol) in dry THF (2.5 mL) was added dropwise via a syringe pump over 2 h. The resulting being suspension was stirred for an additional 2 hours at RT, at which time LC showed that no starting material remained. The mixture was diluted with EtOAc, washed with 0.2N HCl, sat. aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel chromatography (50% dichloromethane/hexanes to 100% dichloromethane to 1% EtOAc/CH2Cl2 to 7% EtOAc/CH2Cl2) and lyophilized in MeCN/water to give the title material (6.2 mgs, 49%). LC (Method B): 2.615 min. HRMS (ESI) calcd for C23H18N5O4S2 [M+H]+ m/z 492.0795. found 492.0828. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.00 (dd, J=8.02, 1.37 Hz, 2H), 7.85 (s, 1H), 7.50-7.56 (m, 3H), 7.14 (s, 1H), 6.71-6.75 (m, 1H), 6.51 (d, J=1.57 Hz, 1H), 5.51 (s, 2H), 4.21 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][CH2:2][C:3]([N:19]1[CH2:18][CH2:17][N:16]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH3:6])[CH2:21][CH2:20]1)=[O:4]
Reactant: COc1cccc(N2CCNCC2)c1OC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cccc(N2CCN(C(=O)CCl)CC2)c1OC
Yield: 98 %

Procedure:
Compound 50A is prepared according to the procedure described for compound 12, using the following reactants: chloroacetyl chloride (150 ml, 1.87 mmol); 1-(2,3-dimethoxyphenyl)piperazine (29A) (416 mg, 1.87 mmol); potassium carbonate (645 mg, 4.67 mmol); methyl ethyl ketone (20 ml).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH2:24]([N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1)[CH3:25]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:31]([C:30]2[N:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=2)=[O:32])=[O:8])[N:6]=1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.76 min; [M+H]+=469.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=O.[P:7]([OH:10])([OH:9])[OH:8].P(Cl)(Cl)Cl>S1(CCCC1)(=O)=O>[CH2:3]([C:4]([P:7]([OH:10])([OH:9])=[O:8])([P:7]([OH:10])([OH:9])=[O:8])[OH:6])[CH2:2][NH2:1]
Reactant: OP(O)O
Reactant: NCCC(=O)O
Solvent: ClP(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A suspension of 3-aminopropionic acid (25 g, 0.280 mol) and phosphorous acid (34.5 g, 0.421 mol) in sulfolane (90 ml) is heated to 75° C. for 30 min. The mixture is cooled to 35-40° C. and then gradually introduced phosphorous trichloride (83 ml, 0.954 mol) while maintaining the temperature at 35-45° C. The mixture is heated to 63-67° C. for 3 hrs, whereby white solid results. It is then cooled to 0-5° C. and quenched by slow addition of water (250 ml) at 0-5° C. over a period of 1 hr. The resulting clear solution is charcoalized and is heated at 100° C. for 3 hrs, cooled to ambient temperature. Cooled the charcoalized solution and stirred for 4 hrs at 0-5° C. The crystallized product is filtered, washed sequentially with chilled water (100 ml), rectified spirit (75 ml) and dried in air oven at 55-60° C. until water content is less than 0.5% w/w. Yield 41.4 g, (62.7%), appearance: white crystalline solid, purity >99.0%.
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.FC(F)(F)C([O-])=O.C([O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1)(=O)C.C(O)C(N)(CO)CO>C1COCC1>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: CC(=O)Oc1ccc(NC(=O)c2ccc(N3CC[NH2+]CC3)cc2)cc1
Reactant: CC(C)COC(=O)Cl
Agent: NC(CO)(CO)CO
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
2 eq of isobutyl-chloroformate and 3.5 eq of Et3N were added to a solution of 4-[4-({[4-(acetyloxy)phenyl]amino}carbonyl)phenyl]piperazin-1-ium trifluoroacetate in dry THF (0.05 M) and the solution was allowed to stir at RT for 3 h under N2. PS-trisamine resin (excess) was added and the reaction mixture was stirred for 16 h. The resin and a white precipitate were filtered off. Excess aqueous NaOH (1 M) was added to the organic solution and the reaction mixture was stirred for 2 h. The organic solvent was removed in vacuo and aqueous HCl (1 M) was added until precipitation of a white solid that was filtered off, washed and dried in vacuo to afford the title compound (90%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:38]=[N:37][N:36]([CH:39]([CH3:41])[CH3:40])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:38]=[N:37][N:36]([CH:39]([CH3:41])[CH3:40])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:27][CH2:28][N:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:30][CH2:31]3)[CH2:24][CH2:25]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(S(C)(=O)=O)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C4CCN(S(C)(=O)=O)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 27 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(1-(methylsulfonyl)piperidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.06 g, 0.18 mmol) in EtOH (2 mL), 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (balloon pressure) for 3-4 hr. On completion of reaction, reaction mass was filtered through celite bed, then filtrate was concentrated under reduced pressure, finally the residue was washed with diethyl ether to provide the desired compound (27% yield). LCMS: 584.35 (M+1)+; HPLC: 96.59% (@ 254 nm) (Rt;4.927); 1H NMR (CD3OD, 400 MHz) δ 8.28 (s, 1H), 7.43 (s, 1H), 6.13 (s, 1H), 5.27 (bs, 1H), 4.55 (s, 2H), 3.94 (d, 2H, J=10.4 Hz), 5.74 (d, 2H, J=10.8 Hz), 3.40 (m, 2H), 3.30 (m, 2H), 2.89 (s, 3H), 2.85 (m, 2H), 2.41-2.25 (m, 12H), 1.90 (m, 2H), 1.56 (d, 6H, J=4.4 Hz).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH:10]([CH3:20])[C:11]([O:18][CH3:19])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CC(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:10]([CH3:20])[C:11]([O:18][CH3:19])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Solvent: CC(C)=O
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(O)cc1

Procedure:
Ethyl 4-(4-hydroxyphenoxy)-3-methoxy-2-pentenoate is prepared by the reaction hydroquinone and ethyl 4-bromo-3-methoxy-2-pentenoate in the presence of base in acetone or the like under reflux.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:21]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22]>O1CCOCC1>[C:21]([C:24]1[CH:25]=[C:26]([S:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)O)c2)cc1
Reaction time: 8 h

Procedure:
2.1 g (0.01 mol) of 3-(4-aminobenzenesulfonyl) acrylonitrile are dissolved in 100 ml dioxane, and 2 ml of pyridine are added thereto. A solution of 2.21 g (0.01 mol) of 3-carboxybenzenesulfonyl chloride in 50 ml dioxane is added portionwise at room temperature and the reaction mixture is held overnight. After filtering and mixing the filtrate with about 4 volumes of water the mixture is left at room temperature for 5 days. White flocs separate which are recovered by filtration and dried, giving 3-[4-(3-carboxybenzenesulfonamido)-benzenesulfonyl]acrylonitrile: ##SPC30##
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][C:7](=O)[C:5]=2[CH:6]=1.C([SiH](CC)CC)C.O>ClCCl>[Cl:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[CH:6]=1
Reactant: O=C1CCCc2sc(Cl)cc21
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Product: Clc1cc2c(s1)CCCC2
Temperature: 25 °C
Reaction time: 84 h

Procedure:
111 g (594 mmol) of 2-chloro-6,7-dihydro-1-benzothiophen-4(5H)-one together with 414 g (3.57 mol) of triethylsilane are initially charged in 1.25 ml of dichloromethane, and 506 g (3.57 mol) of boron trifluoride/ether complex are added at room temperature. The reaction mixture is stirred at room temperature for 84 h and then added to water. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. This gives 90.0 g of 2-chloro-4,5,6,7-tetrahydro-1-benzothiophene.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:29][C@H:28]([CH3:30])[CH2:27][C:26](=[O:31])[CH2:25]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([C@H:24]2[CH2:29][C@H:28]([CH3:30])[CH2:27][C:26](=[O:31])[CH2:25]2)=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@@H](C)C2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@@H](C)C2)c(O)c1
Yield: 64.6 %

Procedure:
A mixture of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-methylcyclohexanone (175 mg, 0.417 mmole) and 175 mg of 5% palladium on carbon-50% water in methanol (8 ml) was stirred under one atmosphere of hydrogen gas until hydrogen uptake ceased. The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated under reduced pressure. Crystallization of the residue in pentane gave 89 mg (64%) of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[Cu][C:11]#[N:12]>C(Cl)Cl>[CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([C:11]#[N:12])=[O:6]
Reactant: C[Si](C)(C)CCC(=O)Cl
Reactant: N#C[Cu]
Solvent: ClCCl
Product: C[Si](C)(C)CCC(=O)C#N
Temperature: 25 °C
Yield: 30.2 %

Procedure:
In a flask were placed 5.0 g (0.032 mole) of 4,4-dimethyl-4-silapentanoic acid chloride and 2.89 g (0.032 mole) of copper(I) cyanide. This mixture was heated at approximately 150°-200° C. for a period of 50 minutes after which it was cooled to ambient temperature. Methylene chloride was added to the reaction mixture which was then filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving 1.5 g of 4,4-dimethyl-4-silapentanoyl cyanide as a residue.
Reaction SMILES: C(Cl)CCl.[C:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=O)[CH2:14][CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH2:30])=[N:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:8]([O:7][C:5]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]([NH:30][NH:29][C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=2)=[O:21])[CH2:16][CH2:17]1)=[O:6])([CH3:9])([CH3:10])[CH3:11]
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)NNc2ccc(F)cn2)CC1
Yield: 80 %

Procedure:
EDC (543 mg, 2.83 mmol) was added portionwise to a solution of 2-(4-Boc-1-piperazinyl)acetic acid (576 mg, 2.36 mmol), 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 0.30 g, 2.36 mmol) and HOBt (32 mg, 0.24 mmol) in dry DCM (15 mL) at RT and stirred for 16 h. The solution was diluted with DCM (20 mL), washed with water (2×20 mL) and dried (Na2SO4). The solvent was evaporated to give the title compound as an off-white solid (667 mg, 80%). LCMS (Method 1): Rt 1.99 min, m/z 354 [MH+].
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=2)[CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2].[OH-].[Li+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=2)[CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(CC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of ethyl 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetate (for a preparation see Intermediate 8) (300 mg, 0.640 mmol) in MeOH (5 mL) was added lithium hydroxide solution (0.768 mL, 0.768 mmol). The resulting mixture was stirred at 40° C. for 2 h, whereupon it was concentrated under vacuum to give the crude lithium carboxylate of 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetic acid (286 mg, 100%) as a white solid which was used in the next step without further purification. LCMS (Formate, 2 min), Rt=1.10 min, MH+=433.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30]1([O:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:30]1([O:36][C:37](=[O:38])[NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:8]3[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:11]4[S:12][CH2:13][CH2:14][CH2:15][N:10]4[N:9]=3)[CH:17]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
3-(3-Pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenylamine (prepared as described in Example 3) (30 mg, 0.097 mmol) was dissolved in dry DCM (1 mL) under nitrogen atmosphere. Triethylamine (0.018 mL, 0.126 mmol, 1.3 eq) and phenylchloroformate (0.015 mL, 0.117 mmol, 1.2 eq) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM and washed with water, dried over Na2SO4 and concentrated to dryness. The residue was taken up with ethylether and filtered to give 27 mg (65%) of [3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenyl]-carbamic acid phenyl ester as white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:9](=[O:11])[CH3:10])=[N:5][CH:6]=[CH:7][N:8]=1)[CH3:2].[Br:12]Br>Br.CO>[BrH:12].[BrH:12].[Br:12][CH2:10][C:9]([C:4]1[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=[CH:6][N:5]=1)=[O:11]
Reactant: CCc1nccnc1C(C)=O
Reactant: BrBr
Agent: Br
Solvent: CO
Product: CCc1nccnc1C(=O)CBr
Temperature: 60 °C
Yield: 122.8 %

Procedure:
To a solution of 6 g (40 mmol) 1-(3-Ethyl-pyrazin-2-yl)-ethanone in 21 ml HBr (33%) and 7 ml methanol was added 2 ml (40 mmol) bromine and the mixture was heated to 60° C. for 3 h. After removal of the volatiles under reduced pressure the residue was washed with diethyl ether and ethyl acetate. 6.4 g (41%) of the title compound was obtained as grey solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)=[O:22])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[CH3:37][S:38](Cl)(=[O:40])=[O:39].CCN(C(C)C)C(C)C>>[CH3:37][S:38]([N:17]1[CH2:18][CH2:19][N:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]3[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)=[O:22])=[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=2)[CH2:15][CH2:16]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CC1CCN(c2cc(N3CCNCC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(N3CCN(S(C)(=O)=O)CC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 90.5 %

Procedure:
The procedure of Example 17 was followed using 40.0 mg (0.0546 mmol) of 5-cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amide tris(trifluoroacetic acid salt) (as prepared in Example 16), 7.6 μL (0.0655 mmol) of is methanesulfonyl chloride and 47.6 μL (0.716 mmol) of DIEA. Chromatography on a 2-g silica SPE column with 5-10% EtOAc-dichloromethane followed by concentration from EtOAc-hexane (1:1, 2 mL) afforded 23.3 mg (91%) of the title compound as a crystalline yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.59 (br s, 1H), 8.33 (d, 1H, J=8.8 Hz), 7.22, 7.25 (AB q, 2H, J=3.7 Hz, partially obscured by CHCl3 peak), 6.79 (d, 1H, J=2.7 Hz), 6.73 (dd, 1H, J=8.8, 2.7 Hz), 3.39-3.41 (m, 4H), 3.25-3.27 (m, 4H), 2.98-3.01 (m, 2H), 2.84 (s, 3H), 2.70-2.76 (m, 2H), 1.83-1.87 (m, 2H), 1.50-1.65 (m, 1H), 1.42-1.58 (m, 2H) and 1.08 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C23H29N5O4S, 472.2 (M+H), found 472.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[Cl:30]N1C(=O)CCC1=O.[OH-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[Cl:30])[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4nccc34)CC2=O)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(Cl)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-4-((R)-1-(6-bromopyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.01 (111 mg, 0.242 mmol) in acetonitrile (2.4 mL) was added N-chlorosuccinimide (38.8 mg, 0.290 mmol). The solution was stirred at room temperature for 3 h. The reaction was poured into 1N NaOH and extracted with dichloromethane. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to afford (R)-4-((R)-1-(6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.36, which was used without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[CH:11].CCCCCC.C([Li])CCC.Br[CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33]
Reactant: C#CCCOC1CCCCO1
Reactant: CC/C=C\C/C=C\CCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\CCCC#CCCOC1CCCCO1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A solution of 1-(tetrahydropyran-2-yloxy)-3-butyne (2.25 g, 14 mmol) in dry THF (15 ml) was treated at -50° C. with n-butyllithium hexane solution (11 ml, 17.5 mmol). After 15 min at -30° C., the mixture was kept at room temperature for 30 min. The mixture was then treated at 0° C. with 5 (3.0 g, 13.8 mmol) dissolved in 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidine (DMPU) (15 mL) during 30 min. The reaction mixture was stirred 12 hr. at room temperature and quenched with saturated NH4Cl solution (30 ml). The product (6) was removed with ether (3×50 ml) and purified by silica-gel flash chromatography (2.2 g, 55% yield). 1H NMR (200 MHz) δ5.36 (m, 4H, CH=CH), 4.64 (m, 1H, CH-2'), 3.81 (m, 2H, CH2 -6' and 1), 3.54 (m, 2H, CH2 -6' and 1), 2.78 (dd, J=6.0, 6.0 Hz, 2H, =CH--CH2 --CH=), 2.47 (m, 4H, CH2 -2, and -5), 2.15 (m, 4H, CH2 -7, and -13), 1.8-1.4 (m, 8H, CH2 -6, -3', -4', and -5'), 0.96 (t, J=7.5, 7.6 Hz, 3H, CH3). 13C NMR (100.6 MHz) δ: 131.8 (12), 128.9 (9, 11), 127.2 (8), 98.7 (2'), 81.0 (3), 76.6 (4), 66.2 (1), 62.2 (6'), 33.4 (2), 30.6 (3'), 28.9 (7), 26.2 (6), 25.5 (14), 25.4 (4'), 20.5 (5), 20.2 (13), 18.3 (5'), 14.3 (10). MS [EI, m/z (%)] 159 (7), 131 (9), 119 (8), 117 (9), 105 (8), 93 (11), 91 (16), 86 (12), 85 (100), 79 (18), 77 (11), 67 (36), 57 (16), 55 (15), 43 (29), 42 (16), 41 (51), 40 (24).