Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][CH:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[O:28])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethylbenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=8.0 Hz, 3 H) 1.23-1.69 (m, 11 H) 1.77 (m, 4 H) 1.99 (m, 2 H) 2.20 (s, 3 H) 2.69 (q, J=7.3 Hz, 2 H) 3.75 (s, 1 H) 3.97 (t, J=14.2 Hz, 2 H) 4.54 (t, J=8.1 Hz, 1 H) 7.57-7.81 (m, 3 H) 8.12 (d, J=7.8 Hz, 1 H) 8.17 (s, 1 H) 8.61 (s, 1 H). [M+H] calc'd for C28H37F2N7O2, 542; found 542.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.O(S(C)(=O)=O)S(C)(=O)=O.C(O)(=O)C(O)=O.[NH2:52][C:53]1[CH:54]=[CH:55][C:56](=[O:60])[N:57]([CH3:59])[CH:58]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:52][C:53]2[CH:54]=[CH:55][C:56](=[O:60])[N:57]([CH3:59])[CH:58]=2)[C:9]2[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)ccc1=O
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(Nc1ccc(=O)n(C)c1)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a stirred solution of Ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (Step 1.3) (423 mg, 1.020 mmol) and triethylamine (1.42 mL, 10.20 mmol) in CH2Cl2 under Ar was added Ms2O (355 mg, 2.039 mmol) at −10° C. The reaction mixture was stirred for 30 min at this temperature. 5-Amino-1-methyl-2(1H)-pyridinone oxalate salt (218 mg, 1.020 mmol) was added at 30° C. After 1 hr, the reaction mixture was quenched with a saturated aq. NaHCO solution, and extracted with CH2Cl2. The combined organic layers were washed a saturated aqueous solution of NaHCO3, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 1-2%) to afford the title product (147 mg, 0.282 mmol, 28% yield) as a greenish solid. tR: 4.68 min (HPLC 1); tR: 1.06 min (LC-MS 2); ESI-MS: 521 [M+H]+ (LC-MS 2); Rf=0.56 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cccnc2)cc1C=O
Yield: 32 %

Procedure:
N1 is prepared according to a method similar to Method A. Commercially available 3-formyl-4-methoxyphenylboronic acid (1.66 g, 9.22 mmol) is dissolved in 56 mL toluene and 14 mL ethanol. 3-Bromopyridine (0.98 mL, 10.2 mmol) is added followed by cesium carbonate (3.0 g, 9.21 mmol). Nitrogen is bubbled through the mixture for 10 minutes, then palladium tetrakistriphenylphosphine (0.53 g, 0.46 mmol) is added and nitrogen bubbling is resumed for another ten minutes. The mixture is heated to reflux for 5 hours. The mixture is allowed to cool and is filtered through Celite. The Celite pad is washed with ethyl acetate and methylene chloride. The filtrate is pumped dry and the residue is chromatographed on silica gel using a gradient elution of methanol/methylene chloride. 2-Methoxy-5-pyridin-3-yl-benzaldehyde (N1) is obtained (0.635 g, 2.98 mmol; 32% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:12](=[O:14])[CH3:13])=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Cc1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CC(C)C)cc1
Yield: 67.2 %

Procedure:
70.0 g (0.47 mol) of p-isobutylaniline was dissolved in 126 ml of glacial acetic acid. 59.9 g (0.58 mol) of acetic anhydride was then added dropwise to the solution at a temperature of 30° C. After the completion of dropwise addition, the reaction mixture was then allowed to undergo reaction at a temperature of 40° C. for 1 hour. The reaction solution was then poured into 500 ml of water. The resulting crystal was filtered off, washed with water, and then dried. The crystal thus obtained was then recrystallized from a mixture of 140 ml of toluene and 700 ml of n-hexane to obtain 60.4 g (yield: 67.3%) of p-isobutylacetanilide. The melting point of the crystal was from 124.5° C. to 125.0° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:18]=[O:19].O>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:18]=[O:19])=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1nc(Br)ccc1I
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1nc(Br)ccc1C=O
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 6-bromo-3-iodo-2-methoxypyridine (1.0 g) in diethyl ether (38 mL) was cooled to −80° C. in a nitrogen atmosphere, and n-butyllithium (2.6 M, 0.735 mL) were added dropwise. After stirring at the same temperature for one hour, N,N-dimethylformamide (0.62 mL) was added dropwise. The mixture was stirred at the same temperature for one hour and water was added to the reaction system, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=94:6→9:1) to give 6-bromo-2-methoxynicotinaldehyde as a colorless powder (618 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9](OC)(=[O:12])[C:10]#[CH:11]>>[OH:12][C:9]1[CH:10]=[CH:11][C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[N:1]=1
Reactant: NC1=CC(=O)CCC1
Reactant: C#CC(=O)OC
Product: O=C1CCCc2nc(O)ccc21
Yield: 21.3 %

Procedure:
A mixture of 3-amino-2-cyclohexen-1-one (25.0 g, 224.9 mmol) and methyl propiolate (23.6 g, 281 mmol) was heated to reflux for 1 h. The mixture was cooled and the solid was collected by filtration, washing with THF, to give 7.8 g (21%) of the title compound as a yellow solid. [M+H] calc'd for C9H9NO2, 164. found 164.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH:12]=[CH:13][CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>CN(C)C=O>[OH:1][C:2]([C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH:17]([CH3:18])[CH3:19])=[CH:21][CH:22]=1)([CH2:11][CH:12]=[CH:13][CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC=CCC(O)C(=O)c1ccccc1
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CCC(O)(C(=O)c1ccccc1)C(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
2-Hydroxy-3-propenylpropiophenone (2.4 grams) is dissolved in 30 ml of dimethylformamide and 0.6 gram of 50% sodium hydride is added thereto little by little at room temperature with stirring. The mixture is stirred for one hour more at the same temperature and 2.4 grams of p-isopropylbenzoyl chloride is dropped thereinto with ice cooling. The mixture is stirred at room temperature for one hour, 0.6 gram of 50% sodium hydride is added thereto, the mixture is heated at 60° to 70° C. for one hour, cooled, and poured into ice water. This is extracted with ethyl acetate, the extract is washed with water, dried with anhydrous magnesium sulfate, the solvent is evaorated therefrom, and the resulting crystals are washed with n-hexane to give 3.6 grams of 2-hydroxy-3-propenyl-alpha-p-isopropylbenzoylpropiophenone, pale yellow powder, melting point 108° to 110° C.
Reaction SMILES: C[O-].[Na+].CO[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[SH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].Cl>CO>[SH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7]
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Temperature: 150 °C
Yield: 79.7 %

Procedure:
To a solution of 4.3 ml of 0.5 M sodium methoxide in methanol was added 75 mg of 4-mercapto-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester and 181 mg of glycine. The mixture was heated to 150° C. for 10 minutes using a CEM Discover microwave reactor (City, State). The resultant solution was cooled, and acidified with 1 N HCl solution to produce a yellow precipitate. The precipitate was collected by filtering the solution through a (medium) porous buchner filter funnel, and triturated with methanol to give 68 mg of product; MS (−): m/z 353.02 (M−1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(#N)C>C(N(CC)CC)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:37](=[O:46])[C:38]2=[CH:45][CH:44]=[CH:43][CH:42]=[C:39]2[C:40]1=[O:41])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 13.4 %

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2.1 g), ethyl 2-bromo-9-phthalimidononanoate (3 g), acetonitrile (100 ml) and triethylamine (0.96 g) is heated at 80° C. for 3 days. After evaporation of the solvent, ethyl acetate (200 ml) and water (150 ml) are added to the residue. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (2:1-1:1) as an eluent. Evaporation of the first eluate gives tert-butyl 3(S)-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.6 g) as a colorless oil.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].CN(C)/[CH:13]=[CH:14]/[C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=O>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:1]([C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=3)[C:6]#[N:7])[N:2]=[CH:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(F)cc1
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nccc2-c2ccc(F)cc2)c1
Yield: 32 %

Procedure:
The title compound was prepared in 32% yield from 2-hydrazinylisonicotinonitrile (PREPARATION 2) and (E)-3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one according to the procedure for the preparation of Example 26, part B. 1H NMR (500 MHz, CDCl3) δ 8.36 (d, 1H, J=4.8 Hz), 8.0 (s, 1H), 7.7 (s, 1H), 7.37 (d, 1H, J=3.8 Hz), 7.25 (d, 2H, J=5.8), 7.0 (t, 2H, J=8.7 Hz, 1H), 6.45 (s, 1H). [M+H] Calc'd for C15H9FN4, 265. Found, 265.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-])=O.[H][H]>[Pd].CO>[NH2:8][C:7]1[C:6]([CH3:11])=[CH:5][C:4]([C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])=[CH:3][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1cc(C(=O)N2CCOCC2)cc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)N2CCOCC2)cc(C)c1N

Procedure:
10% Palladium on carbon (100 mg) is added to a solution of (3,5-dimethyl-4-nitrophenyl)(morpholino)methanone (1.3 g) in methanol (10 mL) and the mixture is hydrogenated for 3 hours under 2 bar hydrogen pressure. Then the catalyst is filtered off and washed with methanol. The combined mother liquors are concentrated to give the title compound. Yield: 1.1 g; LC (method 20): tR=1.94; Mass spectrum (ESI+): m/z=235 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][N:27]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc2cc(C3=NCC4(CCN(S(C)(=O)=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (82 mg) and methanesulfonyl chloride (100 μL) in tetrahydrofuran (3 ml) was added triethylamine (100 μL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, and water was added. The precipitated crystals were collected by filtration, and washed with water. The obtained crystals were recrystallized from tetrahydrofuran to give the title compound (42 mg, yield 36%) as colorless crystals. melting point 251° C.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:10].N1C=CC=CC=1>O>[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14](=[N:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:10]
Reactant: CCOC(=O)CC(=O)c1ccccn1
Reactant: NN1CCCC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CC(=NN1CCCC1=O)c1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
Place 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem., 1969, 9(2), 58; 155.6 g, 1.14 mol) in a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-oxo-3-pyridin-2-yl-propionic acid ethyl ester (Preparation 3-A; 200 g, 1.04 mol) and pyridine (400 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (500 mL) and extract with toluene (2×500 mL). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield 280 g (98%) of the subtitled compound as a dark oil. MS ES+ m/e 276 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:19])[O:15][CH2:14][C:13]([CH3:18])([CH2:16]O)[CH2:12][O:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:9][C:10]1([CH3:19])[O:15][CH2:14][C:13]([CH3:18])([CH2:16][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:12][O:11]1
Reactant: Oc1cccc(Br)c1
Reactant: CC1(CO)COC(C)(C)OC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(COc2cccc(Br)c2)COC(C)(C)OC1
Temperature: -2 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
To a mechanically stirred mixture of 3-bromophenol (26.14 g, 0.1511 mol), 2,2,5-trimethyl-5-hydroxymethyl-1,3-dioxane (31.98 g, 0.20 mol), triphenylphosphine (59.32 g, 0.226 mol), and THF (250 mL), cooled to −2° C., a solution of diisopropyl azodicarboxylate (DIAD), 4.6 mL, 0.2265 mol) in THF (50 mL) was added dropwise over 45 min, and the mixture was allowed to warm up to room temperature. After 3 days, THF was removed, and the residue was stirred in a mixture of toluene and heptane (1:1, 300 mL), and filtered. The solids were washed with the same mixture of solvents (200 mL), and the combined filtrates were washed with dilute sodium hydroxide solution, water, and saturated sodium chloride solution, dried, and concentrated. The residue was chromatographed over silica gel. Elution with toluene-heptane (1:1) removed some unreacted triphenylphosphine. The product came in toluene-heptane (3:1) eluates and, on standing with pentane, solidified, 40.69 g (85% yield), m.p. 67-70° C. Mass spec: m/z 314, 316 (M+). Anal Calcd for C14H19BrO3: C, 53.34; H, 6.08; Br, 25.35%. Found: C, 53.37; H, 5.97; Br, 25.35%.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:19][S:20][CH2:21][CH2:22][CH2:23][OH:24].[Br:25][C:26]1[CH:45]=[CH:44][C:29]([NH:30][C:31]2[C:40]3[C:35](=[CH:36][C:37](O)=[C:38]([O:41][CH3:42])[CH:39]=3)[N:34]=[CH:33][N:32]=2)=[C:28]([F:46])[CH:27]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[Br:25][C:26]1[CH:45]=[CH:44][C:29]([NH:30][C:31]2[C:40]3[C:35](=[CH:36][C:37]([O:24][CH2:23][CH2:22][CH2:21][S:20][CH3:19])=[C:38]([O:41][CH3:42])[CH:39]=3)[N:34]=[CH:33][N:32]=2)=[C:28]([F:46])[CH:27]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Reactant: CSCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCSC
Temperature: 5 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
1,1′-(Azodicarbony)dipiperidine (1.56 g, 6.2 mmol) followed by 3-(methylthio)-1-propanol (0.32 ml, 3 mmol) was added to a mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0 mmol), (prepared as described for the starting material in Example 48), and tributylphosphine (1.42 mL 6.1 mmol) in methylene chloride (20 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then for 18 hours at ambient temperature. The insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methanol (100/0 increasing to 95/5) to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylthiopropoxy)quinazoline (400 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[C:12](Cl)(Cl)=[S:13].O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][N:7]=[C:12]=[S:13]
Reactant: COc1ccccc1CCN
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1CCN=C=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 2-methoxyphenethylamine (1.98 g) in diethylether (20 ml) was added dropwise under ice-cooling thiophosgene (1.54 g). The mixture was stirred at room temperature for 1 hour. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-methoxyphenethyl)isothiocyanate (1.80 g, yield: 71%) as brown oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Li]CCCC.[C:15]([O:19][C:20](=[O:30])[NH:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[N:23]=1)([CH3:18])([CH3:17])[CH3:16].CN([CH:34]=[O:35])C>C1COCC1>[C:15]([O:19][C:20](=[O:30])[NH:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH:34]=[O:35])=[C:24]([Cl:29])[N:23]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Cl)n1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C=O)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylethylamine (7.4 mL, 53.2 mmol) in THF was added n-BuLi (18.8 mL, 47.1 mmol, 2.5 M solution in hexanes) at −78° C., and allowed to stir at 0° C. of 30 minutes. The reaction mixture was again cooled to −78° C. and a solution compound tert-butyl(4,6-dichloropyridin-2-yl)carbamate (4.0 g, 15.2 mmol) in THF (20.0 mL) was added dropwise and stirred for 1 h at the same temperature. After 1 h, DMF (8.08 g, 36.7 mmol) was added at the same temperature and stirred for 30 minutes. After confirming the completion of starting material by TLC, the reaction mixture was quenched with saturated ammonium chloride solution extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to get crude product which was purified by column chromatography (hexanes:ethyl acetate=4:1) to afford product. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.22 (s, 1H), 7.95 (s, 1H), 1.47 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([NH:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])=[C:20]2[CH:19]=1>C(#N)C.CCOC(C)=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([NH:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][OH:4])[CH2:32][CH2:31]3)=[O:28])=[C:20]2[CH:19]=1
Reactant: OCCBr
Reactant: O=C(NC1CCNCC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC1CCN(CCO)CC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 4 h
Yield: 7.3 %

Procedure:
2-Bromoethanol (18 mg, 0.14 mmol) was added to stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (50 mg, 0.12 mmol) (Example-32) in acetonitrile (0.5 mL) and stirring was continued at 70° C. for 4 h. The reaction mixture was diluted with EtOAc, washed the organic layer with water and dried over anhydrous sodium sulphate, concentrated under reduced pressure to afford the crude product, which was purified by Preparative HPLC [Column: 21.2×150×5 um, waters×bridge C-18, Mobile phase-A: 0.1% TFA in water, B: ACN, Gradient (Time/% B): 0/20, 2/30, 1870 and Flow rate: 20 mL/min] to afford 4.1 mg of the title compound.
Reaction SMILES: Br[CH2:2][CH:3]=[CH2:4].[N:5]1([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C>ClCCl>[CH2:2]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)[CH2:6][CH2:7]1)[CH:3]=[CH2:4]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN1CCCN(c2ccc(C(=O)OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.5 %

Procedure:
3-Bromoprop-1-ene (0.433 mL, 5.00 mmol) was added to a stirred solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (1.242 g, 5 mmol) and DIPEA (2.183 mL, 12.50 mmol) in dichloromethane (20 mL). The reaction mixture was stirred under nitrogen at room temperature for 24 h. This was diluted with dichloromethane (20 mL), washed with water (2×25 ml) and saturated sodium chloride solution (20 ml), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-allyl-1,4-diazepan-1-yl)benzoate (0.700 g, 48.5%) as a yellow oil.