Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O.[OH-].[K+].Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>CN(C=O)C>[Br:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[N:8]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(CCl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.3 %

Procedure:
4-Nitro-1H-indazole (1.0 g, 6.1 mmol) and N-bromosuccinimide (1.1 g, 6.4 mmol) were mixed with anhydrous DMF (10 mL) in a 20 mL vial. The reaction was stirred at ambient temperature for 5 minutes. KOH (1.1 g, 18.3 mmol) and 2-(chloromethyl)-6-methylpyridine hydrochloride (1.4 g, 7.6 mmol) were added to the vial and the reaction mixture was stirred for 18 hours. The product was precipitated from solution by addition of H2O (10 mL) to the reaction mixture. The solids were collected vacuum filtration, washed with H2O and dried under vacuum to afford 3-bromo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (1.7 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[O:53][N:52]=[C:51]2[CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)[CH:56]=[CH:57][C:50]=12>CN(C=O)C>[N:49]1[O:53][N:52]=[C:51]2[CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)[CH:56]=[CH:57][C:50]=12
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc3nonc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3nonc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 19.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-benzo[1,2,5]oxadiazol-5-yl-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.005 g of product in 18% yield: LCMS (ESI) m/z 400 (MH+).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[Cl:25][CH2:26][CH2:27][NH2:28].[C:29]1([C:35]2([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH2:43][C:42]3[N:41]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[N:40]=[C:39]([C:52](O)=[O:53])[C:38]=3[CH:37]=[CH:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.C(N(CC)CC)C>[Cl:25][CH2:26][CH2:27][NH:28][C:52]([C:39]1[C:38]2[CH:37]=[CH:36][C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH2:43][C:42]=2[N:41]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[N:40]=1)=[O:53]
Reactant: C[Si](C)(C)CCOCn1nc(C(=O)O)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Reactant: NCCCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1nc(C(=O)NCCCl)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 20 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
0.677 g of 1-hydroxybenzotriazole hydrate, 0.958 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.16 g of 2-chloroethylamine hydrochloride and 1.4 cm3 of triethylamine are successively added to a solution of 1.8 g of 6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole-3-carboxylic acid in 300 cm3 of dichloromethane. After stirring the reaction mixture for about 4 hours at a temperature in the region of 20° C., it is washed with three times 60 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: cyclohexane/ethyl acetate (85/15 by volume)], 1.2 g of 6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole-3-carboxylic acid (2-chloroethyl)amide are thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1.[F:14][C:15]([F:30])([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)[C:16]([NH:18][NH2:19])=O.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:30][C:15]([F:14])([C:16]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 130 °C
Yield: 61.8 %

Procedure:
A mixture of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-pyridazine (step d) (4.57 g, 23.6 mmol) and difluoro-quinolin-6-yl-acetic acid hydrazide (step c) (5.60 g, 23.6 mmol) in n-butanol (125 mL) was heated to 130° C. overnight. The mixture was cooled to room temperature, followed by aqueous work up using AcOEt and a solution of K2CO3. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography (first chromatography: CH2Cl2 100% and CH2Cl2/MeOH:88/12 followed by another column with toluene/iPrOH/NH4OH:85/15/2) to give the title compound (5.5 g, 62%). M.p=199.7° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([OH:18])=O)[C:7]3[CH:12]=[N:11][N:10]([CH:13]([CH3:15])[CH3:14])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.ON1C2N=CC=CC=2N=N1.[NH2:29][CH2:30][C:31]1[C:32](=[O:42])[NH:33][C:34]([CH3:41])=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38].CN1CCOCC1.C(Cl)CCl>CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([NH:29][CH2:30][C:31]3[C:32](=[O:42])[NH:33][C:34]([CH3:41])=[CH:35][C:36]=3[C:37]([F:38])([F:39])[F:40])=[O:18])[C:7]3[CH:12]=[N:11][N:10]([CH:13]([CH3:14])[CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C(F)(F)F)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(C3CC3)nc21
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(F)(F)F)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 19 from 6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.12 g, 0.489 mmol), 1-hydroxy-7-azabenzotriazole (0.100 g, 0.734 mmol), 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)-2(1H)-pyridinone (0.154 g, 0.636 mmol, DMSO (3.0 mL), N-methylmorpholine (0.215 mL, 1.957 mmol), and EDC (0.141 g, 0.734 mmol) The crude solid was purified by silica gel chromatography (eluent: gradient 5-100% of 10% 2M NH3 (in MeOH/DCM) and DCM) and the collected product dried in vacuum oven for 5 h. The final product was collected as 0.112 g (50%). LCMS E-S (M+H)=434.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.12 (m, 4 H), 1.47 (d, J=6.82 Hz, 6 H), 2.20-2.33 (m, 4 H), 4.34-4.54 (m, 2 H), 5.12 (quin, J=6.63 Hz, 1 H), 6.33 (s, 1 H), 7.39 (s, 1 H), 8.18 (s, 1 H), 8.70 (t, J=4.04 Hz, 1 H), 12.43 (s, 1 H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([O:16]C)=O)[CH2:3]1.[CH3:18][NH2:19]>CO>[CH3:18][NH:19][C:14]([CH:4]1[CH2:3][C:2](=[O:1])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5]1)=[O:16]
Reactant: CN
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Solvent: CO
Product: CNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A mixture of 100 g (0.43 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519 (1961)], 500 ml methanol and 100 g (3.2 mole) of methylamine was heated at 100° C. in a pressure reactor for 16 hours. The reaction mixture was cooled and the ammonia and methanol were removed under pressure. The residue was taken up in dichloromethane and washed 3×100 ml 1N sodium hydroxide. The organic layer was dried over magnesium sulfate and the solvent removed at reduced pressure to give 88.3 g of N-methyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as a white solid, mp 82.5-83.0° C.
Reaction SMILES: [CH2:1]([OH:10])[C:2]([CH2:4][O:5]P(O)(O)=O)=[O:3].[N:11]([CH:14]([CH2:17][OH:18])[CH:15]=[O:16])=[N+:12]=[N-:13].[OH-].[Na+].CO>C(O)C(N)(CO)CO>[N:11]([C@H:14]([CH2:17][OH:18])[C@H:15]([OH:16])[C@@H:1]([OH:10])[C:2](=[O:3])[CH2:4][OH:5])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=NC(C=O)CO
Reactant: O=C(CO)COP(=O)(O)O
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=N[C@H](CO)[C@H](O)[C@@H](O)C(=O)CO
Reaction time: 48 h
Yield: 30 %

Procedure:
DHAP (0.5 mmole) was added to an aqueous solution of 2-azido-3-hydroxypropanal (1 mmole in 40 ml) and the pH value adjusted to 7.0 with 10N NaOH. To this solution was added rhamnulose-1-phosphate aldolase from E. coli (4 g), which had been treated with egg white lysozyme (40 mg) in Tris buffer (pH 7.5, 25 ml) for one hour at 35° C., to form a mixture and the mixture stirred slowly for two days. The stirred mixture was adjusted to a pH value of 4.7, and acid phosphatase (400 units) added. The resulting mixture was incubated at 37° C. for 48 hours, neutralized to a pH value of 7.0 and lyophilized. The residue was treated with MeOH and filtered to remove the insoluble material. The MeOH was removed under reduced pressure and the crude product purified with silica gel column chromatography (CHCl3 :MeOH=6:1) to give 5-azido-5-deoxy-D-xylo-hexulose in 30 percent yield.
Reaction SMILES: C(N(CC)CC)C.C[C@@H]1C2C(=CC=CC=2)CCN1.[Cl:19]C1C(C)=C(C)N=C(NC2C=CC(F)=CC=2)N=1.[CH3:36][C:37]1[C:38]([N:52]2[CH2:61][CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C@H:53]2[CH3:62])=[N:39][C:40]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=[N:41][C:42]=1[CH3:43]>C(O)CO>[ClH:19].[CH3:36][C:37]1[C:38]([N:52]2[CH2:61][CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]2[CH3:62])=[N:39][C:40]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=[N:41][C:42]=1[CH3:43]
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(Cl)c1C
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3[C@H]2C)c1C
Agent: C[C@H]1NCCc2ccccc21
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 81.1 %

Procedure:
23 ml of triethylamine and 16 g (108.5 mmole) of (R)-(+)-1-methyl-1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to 75 ml of ethylene glycol. 25.7 g (101.8 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 135° C. for 28 hours under refluxing to prepare (R)-(+)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 24 to obtain 33 g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-pyrimidine hydrochloride.
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH:25]1([B-](F)(F)F)[CH2:27][CH2:26]1.[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([CH:25]2[CH2:27][CH2:26]2)[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: F[B-](F)(F)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CC1
Temperature: 110 °C
Yield: 8 %

Procedure:
To a microwave vial was added 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (15 mg, 0.037 mmol, from peak 1 from Example 167, step 4), potassium cyclopropyltrifluoroborate (8 mg, 0.06 mmol, from Frontier Scientific, item # C10298), potassium phosphate (23 mg, 0.11 mmol), and tetrakis(triphenylphosphine)palladium (4.2 mg, 0.0036 mmol) and then toluene (0.3 mL)/water (0.1 mL). The vial was sealed and degassed with N2 three times. The reaction was heat at 110° C. for 20 h. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.1 mg, 8%). The product was isolated as a single enantiomer. LCMS calculated for C19H23ClN5O (M+H)+: m/z=372.2; Found: 372.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C1C=C([C:18]23[CH2:27][CH:22]([O:23][C:24]2([CH3:26])[CH3:25])[N:21]([CH3:28])[CH2:20][CH2:19]3)C=CC=1.[CH2:31](C(C)=O)C>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:18]2([C:24]([CH3:25])([CH2:26][CH3:31])[OH:23])[CH2:19][CH2:20][N:21]([CH3:28])[CH2:22][CH2:27]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCC(C)=O
Reactant: COc1cccc(Br)c1
Reactant: CN1CCC2(c3cccc(C(F)(F)F)c3)CC1OC2(C)C
Product: CCC(C)(O)C1(c2cccc(OC)c2)CCN(C)CC1

Procedure:
4-(3'-Methoxyphenyl)-α,1-dimethyl-α-ethyl-4-piperidinemethanol was prepared from 3-bromoanisole by the procedure described in Example 2 except that methyl ethyl ketone (2-butanone) was used in place of acetone in the preparation of III; m.p. 134°-135°; NMR (in CDCl3): τ2.6-3.3 (m, 4H); 6.2 (s, 3H); 7.2-8.3 (m, 12H); 8.6 (quartet, 2H); 9.0 (s, 3H) and 9.2 (t, 3H). Anal. Calcd. for C17H27NO2 : C, 73.61; H, 9.81; N, 5.05. Found: C, 73.73; H, 9.69; N, 5.17.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][C:12]1([C:42]([O:44]C)=[O:43])[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@@H:30]4[C:34]4[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=4[F:41])=[CH:25][C:24]=23)=[O:19])[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl>O.C1COCC1.CO>[C:4]([O:8][C:9]([NH:11][C:12]1([C:42]([OH:44])=[O:43])[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@@H:30]4[C:34]4[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=4[F:41])=[CH:25][C:24]=23)=[O:19])[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Reaction time: 6 h
Yield: 87.8 %

Procedure:
LiOH.H2O (43 mg, 1 mmol) in water (2 mL) was added to a stirred solution of (R)-methyl 4-((tert-butoxycarbonyl)amino)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)piperidine-4-carboxylate (120 mg, 0.2 mmol) in THF (6 mL), MeOH (2 mL) and water (2 mL) at 20-35° C. The reaction mixture was stirred for 6 h; thereafter it was concentrated under reduced pressure to afford a crude product. The crude product thus obtained was diluted with cold water, acidified with 2N aqueous HCl solution, extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 100 mg of the title compound as a pale green solid. MS (ESI): m/z 570.2 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[C:10]([NH:11][C:12]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=[C:14]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[F:29])[N:13]=2)=[CH:9][CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([F:29])=[C:22]([C:14]2[N:13]=[C:12]([NH:11][C:10]3[C:5]([C:4]([OH:30])=[O:3])=[CH:6][N:7]=[CH:8][CH:9]=3)[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=2)[CH:27]=1
Reactant: CCOC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Temperature: 25 °C

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-yl-amino]-nicotinic acid ethyl ester (150 mg, 0.35 mmol, 1 eq) in MeOH (5 ml) was added a 1N NaOH(aq) solution (423 μl, 0.42 mmol, 1.2 eq) and the reaction mixture was refluxed for 1 h. The solution was cooled to r.t. and concentrated in vacuo. Water (20 ml) was added to the crude material and the aqueous layer was acidified to pH 4. The solid was filtered, washed with water (2×5 ml) and dried overnight to give 4-[2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ylamino]-nicotinic acid, compound of formula (50) (132 mg, as a cream colored solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](I)[CH3:30]>C(#N)C>[CH2:29]([O:20][C:6]1[C:5]([O:21][CH3:22])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19])[CH3:30]
Reactant: CCI
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCC)c1OC
Temperature: 80 °C
Yield: 45.7 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (90 mg, 0.302 mmol) in acetonitrile was added potassium carbonate (126 mg, 0.906 mmol) and ethyl iodide (141 mg, 0.906 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded title compound as a solid (45 mg, 46%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:22]=2/[CH:32]=[CH:33]/[C:34]([O:36]CC)=[O:35])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:23][C:22]=2/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35])=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2oc(-c3ccccc3)nc2/C=C/C(=O)O)cc1
Yield: 97.6 %

Procedure:
To a mixture of ethyl (2E)-3-[5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]-2-propenoate (0.40 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the precipitated crystals were collected by filtration to give (2E)-3-[5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]-2-propenoic acid as colorless crystals (0.37 g, yield 97%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 209-210° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].Cl[CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C[N-]C>[CH3:6][C:2](=[CH2:1])[C:3]([O:5][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:4]
Reactant: C=C(C)C(=O)O
Reactant: C[Si](C)(C)CCl
Agent: C[N-]C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C)C(=O)OC[Si](C)(C)C
Temperature: 90 °C
Reaction time: 5 h

Procedure:
300 mmol of Methylacrylic acid (MAA) and 200 mmol of chloromethyl trimethylsilane were dissolved in 400 ml of dimethylamide. Potassium carbonate was added to the solution and heated to 90° C. and stirred for 5 hours. Next, the reaction solution was filtered. The filtrate was added to a sodium hydrogen carbonate solution, extracted with ether and pure water respectively, dried, filtered, and concentrated to obtain trimethylsilanylmethyl methylacrylate (TMSA) having the formula (i) below
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]#[N:18])[C:5](=[O:16])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7]=1[CH3:8].[CH3:19][Sn](C)(C)C.O.C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([N:6]2[C:7]([CH3:8])=[C:2]([CH3:19])[CH:3]=[C:4]([C:17]#[N:18])[C:5]2=[O:16])=[CH:10][CH:11]=1
Reactant: C[Sn](C)(C)C
Reactant: Cc1c(Br)cc(C#N)c(=O)n1-c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(=O)n(-c2ccc(F)cc2)c1C
Temperature: 120 °C
Reaction time: 17 h
Yield: 59.6 %

Procedure:
To a solution of 5-bromo-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (200 mg, 0.651 mmol) in N,N-dimethylformamide (2 mL) were added tetramethyltin (582 mg, 3.255 mmol) and tetrakistriphenylphosphinepalladium(0) (22.3 mg, 0.019 mmol), and the mixture was stirred at 120° C. for 17 hr. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to give the title compound (94 mg, 60%) as a white solid.
Reaction SMILES: [CH2:1]([OH:5])[C@H:2]([OH:4])[CH3:3].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[C:6]([O:5][CH2:1][C@H:2]([OH:4])[CH3:3])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Dimethylaminopyridine (82 mg, 0.67 mmol) was added to a solution of (R)-propane-1,2-diol (5.17 g, 67.9 mmol) and trityl chloride (19.2 g 68.9 mmol) in DCM (200 mL) at 0° C. Triethylamine (23.5 mL, 168.6 mmol) was then added dropwise to this mixture. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with 1.0 N aq HCl (50 mL), washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give (R)-1-(trityloxy)propan-2-ol (18.6 g, 86%) as a white solid. 1H NMR (DMSO-d6): δ 7.43-7.22 (m, 15H), 4.64 (d, 1H), 3.78 (m, 1H), 2.94 (dd, 1H), 2.70 (dd, 1H), 1.06 (d, 3H).