Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]4[N:29]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[S:31][CH:32]=4)=[N:24][CH:25]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[N:24][C:23]([O:26][CH2:27][C:28]4[N:29]=[C:30]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[S:31][CH:32]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
After a mixture of ethyl 3-[3-phenyl-1-[2-(2-phenyl-4-thiazolylmethoxy)-5-pyridylmethyl]-1H-pyrazol-4-yl]propionate (603 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (500 mg, yield: 88%). This was recrystallized from acetone-hexane. Melting point: 107–108° C.
Reaction SMILES: Cl[C:2](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(#N)C>[CH3:17][C:16]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:20][N:19]=1
Reactant: CC(=O)NN
Reactant: CCOC(=O)C(Cl)=Nc1ccccc1C
Solvent: CC#N
Product: CCOC(=O)c1nnc(C)n1-c1ccccc1C

Procedure:
The suspension of 10B and acetohydrazide in acetonitrile was refluxed for 2 hours. The solvent was removed. The crude product was purified by flash column (Rf: 0.2, 50% EtOAc/Hexanes). MS (m/z) 246 [M+H]+.
Reaction SMILES: [CH:1](/[C@@H:5]1[C@@H:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11])=[CH:2]\[CH:3]=[CH2:4].CN1C=CN=C1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[F:30][C:31]1[C:38]([F:39])=[CH:37][C:36]([F:40])=[C:35]([F:41])[C:32]=1[CH2:33]O>CC#N>[CH:1](/[C@@H:5]1[C@@H:7]([C:8]([O:10][CH2:33][C:32]2[C:35]([F:41])=[C:36]([F:40])[CH:37]=[C:38]([F:39])[C:31]=2[F:30])=[O:9])[C:6]1([CH3:12])[CH3:11])=[CH:2]\[CH:3]=[CH2:4]
Reactant: OCc1c(F)c(F)cc(F)c1F
Reactant: C=C/C=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: CC#N
Product: C=C/C=C/[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)cc(F)c2F)C1(C)C
Yield: 97.6 %

Procedure:
In a similar way to that described in example 1 part b., 2.38 g (14.3 mmol) of (1R,3R)-3-((E)-buta-1,3-dienyl)-2,2-dimethylcyclopropane-1-carboxylic acid are added with 3.4 ml (43 mmol) of N-methyl imidazole dissolved in 43 ml of CH3CN, and reacted with 3.26 g (17.2 mmol) of tosyl chloride dissolved in 19 ml of CH3CN then with 2.6 ml (14.3 mmol) of 2,3,5,6-tetrafluorobenzyl alcohol dissolved in 16 ml of CH3CN. After purification on silica gel column with 100/1 (v/v) petroleum ether/ethyl ether as eluent, 4.58 g of an oily product with an E/Z ratio of 97/3 and a purity equal to 96.1% are obtained.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[N:24]=[C:23]4[C:18]([CH2:19][CH2:20][CH2:21][NH:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:5]=[CH:4][N:3]=1.[NH2:25][CH2:26][C@@H:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].[F-].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:8][C:7]1[C:2]([NH:25][CH2:26][C@@H:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[N:3][CH:4]=[N:5][C:6]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: Fc1c(Br)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@H](CNc1ncnc(N2CCC(c3ccc4c(n3)NCCC4)CC2)c1F)NC(=O)OCc1ccccc1
Yield: 68.8 %

Procedure:
A mixture of 280 mg (0.72 mmole) of 4-bromo-5-fluoro-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 253 mg (0.86 mmole) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 152 mg (1.00 mmole) of caesium fluoride, 33 mg (0.036 mmole) of tris(dibenzylideneacetone)dipalladium(0), 45 mg (0.072 mmole) of 2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 50 ml of dioxane is heated under reflux for 6 hours. The reaction medium is cooled down then another 125 mg (0.43 mmole) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 152 mg (1.0 mmole) of caesium fluoride, 33 mg (0.036 mmole) of tris(dibenzylideneacetone)dipalladium(0), and 45 mg (0.072 mmole) of 2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl are added and the reaction mixture is heated under reflux for 4 hours, followed by evaporating to dryness under reduced pressure (2 kPa). The residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of heptane-ethyl acetate-methanol from 100-0-0 to 0-100-0 and finally 0-95-5. The product obtained is chromatographed a second time on alumina eluting with a heptane-methylene chloride mixture 50-50 then with an ethyl acetate-diisopropyl ether mixture 50-50. 300 mg (Yield=70%) of expected product is obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH3:22])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: Cc1ccccc1CCN
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccccc1CCNc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 160 °C
Yield: 42.2 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(2-methylphenyl)ethanamine (300 mg, 2.22 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (150 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.33 (s, 3H), 2.82-2.86 (m, 2H), 3.50-3.45 (m, 2H), 5.36 (s, 2H), 5.98 (s, 2H), 6.29 (s, 1H), 6.97 (s, 1H), 7.09-7.22 (m, 4H), 7.43 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[N+:21]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[C:2]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=[O:1])([O-:23])=[O:22]
Reactant: N#Cc1cccc(C(O)c2ccc3ccccc3c2[N+](=O)[O-])c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)c2ccc3ccccc3c2[N+](=O)[O-])c1
Reaction time: 18 h
Yield: 86.4 %

Procedure:
To a solution of 3-[hydroxy(1-nitronaphthalen-2-yl)methyl]benzonitrile (7.37 g, 24.2 mmol) in dichloromethane (70 mL) was added silica gel (30 g) and pyridinium dichromate (13.7 g, 36.3 mmol), and stirred for 18 hours. The reaction mixture was filtered, and the residue was washed with chloroform. The filtrate was concentrated to dryness, and the residue was recrystallized from ethyl acetate, and washed with hexane to give the titled compound as a pale yellow crystal (6.32 g, yield 86%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15].C1COCC1>CCOCC>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Brc1ccccn1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of 15.7 mL of 1.6 M n-butyllithium (25.1 mmol) in anhydrous ether (25 mL) was stirred under Ar at −78° C. and to this was added a solution of 2-bromopyridine (3.97 g, 25.1 mmol) in anhydrous ether (12.5 mL). The resulting orange solution was stirred for 2 h, and trimethyltin chloride in THF (26.0 mmol, 26 and, 1.0 M) added over 30 min. The reaction was stirred for 1 h at −78° C. then warmed to room temperature over 1 h, filtered and the filtrate evaporated. Distillation afforded 3.1 g (51%) of the title compound as a colorless liquid which solidified in the receiver flask. B.p. 65° C./2 mm Hg; Literature B.p. 75° C./4 mm Hg.
Reaction SMILES: C([S@@]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][C@H:9]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[NH2:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][C@H:9]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: Cc1cccc2c1[C@@H](N[S@@](=O)C(C)(C)C)[C@H](C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc2c1[C@@H](N)[C@H](C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of 140 mg of tert-butyl (1S,2R)-1-{[(S)-tert-butylsulfinyl]amino}-7-methylindane-2-carboxylate in 9.1 ml of ethyl acetate was added 0.88 ml of a 4 M hydrogen chloride/ethyl acetate solution, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and to the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 88 mg of tert-butyl (1S,2R)-1-amino-7-methylindane-2-carboxylate.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:31]1[CH2:37][N:36]2[C:38]([CH2:41][CH:42]([OH:44])[CH3:43])=[CH:39][N:40]=[C:35]2[C@H:34]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:33][CH2:32]1>ClCCl>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:31]1[CH2:37][N:36]2[C:38]([CH2:41][C:42](=[O:44])[CH3:43])=[CH:39][N:40]=[C:35]2[C@H:34]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:33][CH2:32]1
Reactant: CC(O)Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
Dess-Martin reagent [1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] (257 mg, 0.605 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-hydroxypropyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (85 mg, 0.202 mmol) in dichloromethane (5 mL) at 0° C., and the mixture was allowed to warm to ambient temperature. After 4 h, the reaction was quenched with saturated aqueous sodium sulfite. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (19 mg). MS 420.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-bromo-4-fluorophenyl)ethanone (15.0 g, 69 mmol) in tetrahydrofuran (200 mL) was treated with sodium borohydride (5.3 g, 138 mmol) at 0° C. After the addition, the ice bath was removed, and the mixture was stirred at room temperature for 30 minutes and at reflux overnight. After cooling, 1N HCl (10 mL) was slowly added and the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with water, and concentrated. The residue was purified by flash chromatography (30% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 220 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2Cl.[NH3:15]>[Cl-].[NH4+]>[OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:15]
Reactant: CC(O)Cn1cnc2c(Cl)ncnc21
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC(O)Cn1cnc2c(N)ncnc21

Procedure:
9-(2-Hydroxy-1-propyl)-6-chloropurine (I, 9 g, 42.5 mmol) was dissolved in saturated methanolic ammonia and ammonium chloride (50 mg). The mixture was heated at 130° in a bomb for 6 hr. The resulting solution was evaporated to dryness and recrystallized from ethanol/acetone. Yield=6.68 g of a colorless crystalline product (81%) mp 193°-194° uv (H2O; pH 5.5) λmax 260 nm TLC in CHl3 :MeOH (5:1) Rf 0.44
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[CH:53][C:52]=1[SH:61].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O.C(#N)C>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[N:6]([CH:36]=[C:3]([CH2:2][S:61][C:52]4[CH:53]=[CH:54][C:55]5[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=5)[N:51]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)=[CH:8][N:9]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(CO)cn34)cn2)CC1
Reactant: Sc1ccc2ccccc2n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(CSc5ccc6ccccc6n5)cn34)cn2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of compound 30a (200 mg, 0.40 mmol) in DCM (2 mL) and DIEA (0.15 mL, 0.80 mmol) was cooled to 0° C. and MsCl (47 μL, 0.60 mmol) was added dropwise. The reaction was stirred at 0° C. for 15 min and the solvents were removed under reduced pressure. The residue obtained was treated with ACN (10 mL), 2-quinolinethiol (74 mg, 0.45 mmol) and K2CO3 (84 mg, 0.61 mmol). The resulting mixture was stirred at 60° C. for 20 h. The reaction was diluted with H2O (20 mL) and extracted with DCM (3×30 mL). The combined organic extracts were washed with brine (20 mL) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (1:0-0:1 DCM/EtOAc) to obtain compound 30b. Mass Spectrum (LCMS, ESI pos.) Calcd. for C34H38N8O3S: 639.3 (M+H). Found 639.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH:28]([NH2:31])([CH3:30])[CH3:29].CCCP(=O)=O>O1CCCC1>[CH:28]([NH:31][C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26])([CH3:30])[CH3:29]
Reactant: CC(C)N
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 83.5 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), isopropylamine (119 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 ul, 318.8 mmol) in tetrahydrofurane (7.00 ml) is stirred for 20 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording N4-isopropyl-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (93 mg, 83.8%) as a white solid. mp.: >250° C. MS: m/z=404.4 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH:41]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:39]=[N:38]2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([N:37]2[CH:41]=[C:40]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([CH2:11][C:12]5[C:13]([F:23])=[C:14]6[C:19](=[CH:20][C:21]=5[F:22])[N:18]=[CH:17][CH:16]=[CH:15]6)=[CH:9][N:10]=4)[N:7]=3)[CH:39]=[N:38]2)[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(Cl)nn12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4ncc(Cc5c(F)cc6ncccc6c5F)n4n3)cn2)CC1
Temperature: 150 °C

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline (Stage 171.2, 264 mg, 0.798 mmol) was dissolved in DME (2.5 mL) in a microwave reactor with 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (see Stage 180.1, 301 mg, 0.798 mmol), and a solution of 2 M Na2CO3 (1.44 mL). Then tetrakis-(triphenylphosphine)-palladium (46.1 mg, 0.040 mmol) was added and the RM was heated at 150° C. for 5 min under microwave irradiations. It was then taken up with EtOAc and washed with 10% Na2CO3 sol. and brine. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM) to afford after evaporation of the solvent the title compound as a pale yellow solid (tR 1.3 min (conditions 2), MH+=546).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].O.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:13][CH3:14])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1c(O)cccc1C(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cccc(O)c1C

Procedure:
A solution of 3-Hydroxy-2-methylbenzoic acid (5.04 g, 33.12 mmol) and p-Toluenesulfonic acid monohydrate (0.741 g, 3.89 mmol) in abs ethanol (150 ml) was refluxed for 16 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with EtOAc (30 ml) and washed with water (20 ml). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH:14]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]#[N:25])=[CH:23][C:18]=2[CH2:17][CH2:16][O:15]1.C(N(CC)CC)C>ClCCl>[O:11]=[CH:12][CH2:13][CH:14]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]#[N:25])=[CH:23][C:18]=2[CH2:17][CH2:16][O:15]1
Reactant: N#Cc1ccc2c(c1)CCOC2CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1ccc2c(c1)CCOC2CC=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dimethylsulfoxide (0.35 mL, 5 mmol) and oxalyl chloride (2M in dichloromethane) (2.2 mL, 4.4 mmol) were stirred in dichloromethane (30 mL) under nitrogen at −78° C. After 10 min, 1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile (0.48 g, 2.4 mmol) in dichloromethane (50 mL) was added dropwise and the solution stirred at −78° C. for 1 h, before triethylamine (2.5 mL, 18 mmol) was added slowly. The reaction was allowed to warm to room temperature and after 2 h the reaction was quenched by addition of water. Removal of the solvent in vacuo yielded the title compound, which was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)([CH3:13])[CH3:12].IC(C)C>C1COCC1>[CH:11]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)([CH3:13])[CH3:12]
Reactant: c1ccc2sccc2c1
Reactant: [Li]C(C)(C)C
Solvent: CC(C)I
Solvent: C1CCOC1
Product: CC(C)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
2-i-Propylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 11.2 mmoles, 6.6 ml), 2-iodopropane (11.2 mmoles, 1.12 ml) and THF (20 ml) with stirring at ambient temperature for 24 hrs. It was isolated as a yellow oil (1.11 g; 85% yield).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12j and 1-methylimidazole