Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([O:16][C:17]([C:19]3[CH:30]=[CH:29][C:22]([C:23]([O:25]CC=C)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH3:15])[CH:5]=[CH:4][C:3]1=2.N1CCOCC1.C(O)C>C1COCC1.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>[CH3:31][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([O:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:29][CH:30]=3)=[O:18])[CH3:15])[CH:5]=[CH:4][C:3]1=2
Reactant: C=CCOC(=O)c1ccc(C(=O)OC(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(OC(=O)c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
A solution of 2.40 g (5.71 mmol) of the ester obtained in Example 59 (b) in 30 ml of THF is treated with mg of tetrakis(triphenylphosphine)palladium(0) and 5 ml of morpholine under the preparation conditions of Example 24(b), to yield 1.94 g (89%) of the expected derivative, melting point 138° C. (αD =-53.2°; c=1, ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C:21]([O-:24])(=[O:23])[CH3:22].[Na+]>CN(C=O)C.O>[C:21]([O:24][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:10](=[O:11])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=[CH:3][C:2]=1[Br:1])(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: CCOc1ccc(C(=O)c2ccc(CBr)c(Br)c2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)c2ccc(COC(C)=O)c(Br)c2)cc1
Temperature: 68 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
To a solution of (3-bromo-4-(bromomethyl)phenyl)(4-ethoxyphenyl)methanone (0.456 g, 1.15 mmol) in 15 mL of DMF was added sodium acetate (0.188 g, 2.29 mmol). After being stirred for 2.5 h at 68° C., the mixture was diluted with 15 mL of H2O and extracted 3× with ethyl acetate. The combined organic layers were washed once with saturated NH4Cl, once with saturated brine and dried over Na2SO4. Concentration under reduced pressure gave 0.412 g of the crude product, which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.95 (d, J=1.2 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.68 (dd, J=1.2, 8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 5.25 (s, 2H), 4.12 (q, J=7.0 Hz, 2H), 1.46 (t, J=7.0 Hz, 3H); MS ESI (m/z) 377 (M+1)+, calc. 376.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=[CH:36][CH:37]=C[C:33]=2[N:32]=N1.CNCC1C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:32]2[CH2:33][CH2:34][CH2:35][CH:36]2[CH3:37])=[O:23])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNCc1ccccc1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCC4C)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), methylbenzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[S:12][C:13](I)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[S:12][C:13]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][C:26]=2[F:28])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: NC(=O)c1cc(I)sc1NC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: NC(=O)c1cc(-c2ccc(F)cc2F)sc1NC(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A suspension of benzyl[3-(aminocarbonyl)-5-iodo-2-thienyl]carbamate (250 mg, 0.622 mmol), 2,4-difluorophenylboronic acid (349 mg, 2.21 mmol), dichlorobis(triphenylphosphine)palladium (21.8 mg, 0.031 mmol), and sodium carbonate (6.22 mL, 12.43 mmol) in 1,2-dimethoxyethane (10 mL) sealed in a 5 mL microwave reaction vessel was purged of oxygen by doing 5 vacuum/argon flush cycles. The reaction solution was heated in a Biotage microwave for five minutes at 100° C. The resulting mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate (20 mL). The layers were separated and the organic layer was washed with saturated sodium bicarbonate (20 mL) and brine (2×20 mL), dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography using a 0-4% methanol/dichloromethane elution to afford the title compound.
Reaction SMILES: [N+:1]([C:4](=[C:13]1[NH:18][CH2:17][CH2:16][CH2:15][S:14]1)[C:5]([O:7][CH:8]([CH3:12])[CH2:9][S:10][CH3:11])=[O:6])([O-:3])=[O:2].[CH3:19][I:20]>>[I-:20].[CH3:11][S+:10]([CH3:19])[CH2:9][CH:8]([O:7][C:5](=[O:6])[C:4]([N+:1]([O-:3])=[O:2])=[C:13]1[NH:18][CH2:17][CH2:16][CH2:15][S:14]1)[CH3:12]
Reactant: CSCC(C)OC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reactant: CI
Product: CC(C[S+](C)C)OC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Product: [I-]

Procedure:
9 was prepared as a yellow solid, m.p.: 113°-114°, by treating 9A with methyl iodide according to the procedure described in Example 1. EXAMPLE 10
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][N:27]=[N+:28]=[N-:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)OC(C)(C)C)CCC2O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)C(CN=[N+]=[N-])C1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-hydroxy-3-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (8.56 mmol, 3.3 g) in DMF (20 mL) was added sodium azide (35.28 mmol, 2.34 g), and the reaction mixture was stirred at 80-90° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with DCM (200 mL), washed with water, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with ethyl acetate in hexanes (1:1) to provide 3-azidomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[C:4]([F:20])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[C:4]([F:20])=[CH:3][C:2]([NH:1][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=3)=[O:30])=[CH:18][C:17]=2[F:19])[CH:12]=[CH:11][N:10]=1
Reactant: Nc1cc(F)c(Oc2ccnc(N)c2[N+](=O)[O-])c(F)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Nc1nccc(Oc2c(F)cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2F)c1[N+](=O)[O-]
Yield: 23.8 %

Procedure:
Method H3 was used with 4-(4-amino-2,6-difluorophenoxy)-3-nitropyridin-2-amine (0.20 g, 0.709 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.16 g, 0.709 mmol) to afford the title compound (0.085 g, 24%). 1H NMR (250 MHz, 6, ppm, DMSO-d6): 6.11 (d, 1H, J=5.7 Hz), 7.28 (s, 2H), 7.46 (d, 2H, J=10.3 Hz), 7.61-7.71 (m, 2H), 8.04 (d, 1H, J=5.7 Hz), 8.09 (d, 1H, J=2.1 Hz), 9.36 (s, 1H), 9.40 (s, 1H). m/z 504.0 [(M+H)+ calcd. for C19H11ClF5N5O4 503.0].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#N)[CH2:11][C:10]([O:14][CH3:15])([O:12][CH3:13])[CH2:9]2)=[CH:4][CH:3]=1.[OH-:18].[Na+].[OH2:20]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]([OH:20])=[O:18])[CH2:11][C:10]([O:14][CH3:15])([O:12][CH3:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COC1(OC)CC(C#N)(c2ccc(F)cc2)C1
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: COC1(OC)CC(C(=O)O)(c2ccc(F)cc2)C1
Yield: 66 %

Procedure:
A solution of Intermediate 308A (1.4 g, 5.95 mmol) in ethanol (20 mL) and H2O (20 mL) was added a10% aq. solution of NaOH (10 mL, 5.95 mmol) and the reaction mixture was heated at reflux for 12 h. The reaction mixture was concentrated under reduced pressure to afford Intermediate 308B (1.0 g, 66% yield) as a gummy solid. The crude product was used in the subsequent reaction without purification. 1H NMR (400 MHz, chloroform-d) δ ppm 7.45 (dd, J=8.94, 5.05 Hz, 2H), 7.09 (t, J=8.66 Hz, 2H), 2.82-3.0 (m, 8H), 2.64-2.72 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:3]=1[C:4]([OH:14])([C:9]#[C:10][CH:11]1[CH2:13][CH2:12]1)[C:5]([F:8])([F:7])[F:6].C(N(CC)CC)C.[C:28](Cl)(Cl)=[O:29]>C1(C)C=CC=CC=1>[Cl:20][C:16]1[CH:17]=[C:18]([F:19])[C:2]2[NH:1][C:28](=[O:29])[O:14][C:4]([C:9]#[C:10][CH:11]3[CH2:13][CH2:12]3)([C:5]([F:6])([F:7])[F:8])[C:3]=2[CH:15]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(F)cc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1Nc2c(F)cc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a stirred cooled (−25° C.) solution of 144 mg (0.47 mmol) of +/−)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 6 mL of toluene was added 0.28 mL (2.0 mmol) of triethylamine followed by 0.62 mL( 1.2 mmol) of a 1.93 M solution of phosgene in toluene over 3 min. The solution was stirred an additional 30 min. at −25° C. after which time it was warmed to ambient temperature and quenched with 0.5 N aq. citric acid. The mixture was extracted once with ether and once with ethyl acetate, and the combined organic extracts were washed sequentially with sat'd aq. NaHCO3, water, and brine. The solution was dried (MgSO4), and concentrated under reduced pressure to afford a tan solid. The crude product was chromatographed on silica gel(elution with 3:1 hexanes-ether) to afford, after concentration, 90 mg (58%) of (+/−)-6-chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.65(br s, 1H); 7.32-7.34(m, 1H); 7.22(d, 1H, J=2.2 Hz); 1.36-1.43(m, 1H); 0.82-0.98(m, 4H). 19F (282 MHz, CDCl3) δ −132.5(s, 1F), −81.1(s, 3F). High resolution mass spec: calculated for C14H9NO2ClF4(M+H)+: 334.0258, found: 334.0244.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([CH:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[CH:33][CH:34]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(NCc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-[2-({2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-phenyl]-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (44.0 mg, 0.231 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.019 g, 18%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (d, J=6.6 Hz, 1H), 7.55-7.47 (m, 3H), 7.38-7.28 (m, 3H), 7.20 (d, J=8.4 Hz, 2H), 6.69-6.64 (m, 2H), 6.37 (d, J=7.7 Hz, 1H), 5.23 (t, J=5.9 Hz, 1H), 4.72 d, J=6.1 Hz, 2H), 3.31 (s, 3H), 3.02-2.95 (m, 5H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 2.10-2.00 (m, 2H), 1.88-1.74 (m, 4H). MS=520 (MH)+.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:22])([O:6]CC)=[O:5])C.[Br:23][Si](C)(C)C>ClCCl>[BrH:23].[P:4]([CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:22])([OH:6])([OH:5])=[O:3]
Reactant: C[Si](C)(C)Br
Reactant: CCOP(=O)(CCCOn1cnc2c(N)ncnc21)OCC
Solvent: ClCCl
Product: Br
Product: Nc1ncnc2c1ncn2OCCCP(=O)(O)O
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a solution of 9-[3-(diethoxyphosphoryl)propoxy]adenine (300 mg, 0.9 mmol) in dry dichloromethane (10 ml), was added bromotrimethylsilane (0.6 ml, 4.5 mmol). After 2 hours at ambient temperature, the solution was evaporated to dryness, the residue treated with methanol and the solution evaporated to dryness again. The solid residue was crystallised from methanol-acetone to afford 9-(3-phosphonopropoxy)adenine, hydrobromide salt, (80 mgs, 24%) m.p. 175°-180° C.. UV: λmax (MeOH) 259 (ε14,050) nm. IR: υmax (KBr) 1692, 1588, 1451, 1416, 1335, 1220, 1061, 1004, 952 cm-1. 1H NMR: δH [(CD3)2SO] 1.6-1.95 (4H, m, CH2CH2P), 4.47 (2H, t, J=6.5 Hz, N--OCH2), 8.46 (1H, s), 8.76 (1H, s), 7.0-10.0 (5H, broad, D2O exchangeable). Found: C, 27.29; H, 3.80; N, 19.64; Br, 21.52%. C8H13N5O4PBr requires: C, 27.13; H, 3.70; N, 19.78. Br, 22.50%.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[CH2:18][CH2:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.ClCC[N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[H-].[K+].O1CCO[CH2:38][CH2:37]1>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][O:23][CH2:37][CH2:38][CH:33]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC[C@H]1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: ClCCN1CCCCC1
Reactant: C1COCCO1
Agent: Cl
Agent: [H-]
Agent: [K+]
Product: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@@H](COCCC3CCCCN3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis-{4-[N,N-Dibenzylamino]cyclohexyl}methan-1-ol (2.851 g, 9.21 mmol) and (2-chloroethyl)piperidine hydrochloride were suspended in 50 mL of dioxane. Potassium hydride (3.16 g, 35% by weight in mineral oil) was added dropwise in suspension in 20 mL of dioxane. The reaction mixture was stirred at room temperature for about 1 hour. The reaction mixture was then warmed to about 70° C. and one equivalent of potassium hydride (1.05 g, 35% by weight in mineral oil) was added dropwise. The temperature was maintained for about 2 hours, after which the conversion was complete. The reaction was cooled to room temperature and quenched with methanol. Solvents were removed under reduced pressure. Acetonitrile was added (200 mL) and the gray brown solid was removed by filtration. The crude was purified by column chromatography on silica gel using 3% (ethanol/ammonium hydroxide=8:1) in dichloromethane. The product was isolated as an orange oil that solidified under vacuum. (2.84 g, 72% yield): ES-MS (m/z) 421.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=2)[NH:5]1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1>O1CCCC1.CN1CCCC1=O>[OH:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:18]1[C:27]3[C:22](=[CH:23][C:24]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COCCOc1ccc2c(-c3c(O)[nH]c4ccc(C(=O)OC)cc34)ncnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
Sodium hydride (58 mg, 1.45 mmol, 60% in oil) was washed with petroleum ether (3×5 mL) and dried in vacuo. The solid was suspended in tetrahydrofuran (3 mL) and methyl 2-oxo-5-indolinecarboxylate (140 mg, 0.73 mmol) in tetrahydrofuran (2 mL) and N-methylpyrrolidinone (2 mL) was added. The reaction mixture was stirred for 30 min at room temperature. A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline (183 mg, 0.77 mmol, described in WO 97/42187) in tetrahydrofuran (2 mL) and N-methylpyrrolidinone (1 mL) was added and the reaction mixture was stirred for 1.5 h at room temperature. The solvent was removed in vacuo and 1 M hydrochloric acid was added. The precipitate formed was filtered off and dried at 40° C. in vacuo over night to give 150 mg (99% yield) of the title compound as an orange solid: MS (AP+) m/z 394.2 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[N:9][OH:10])=[CH:4][N:3]=1.ClN[C:13](=O)[CH2:14][CH2:15][C:16](N)=O.C(OCC)C.[CH3:25][Si:26](C#C)([CH3:28])[CH3:27]>CN(C=O)C.C(N(CC)CC)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:14]([C:15]#[C:16][Si:26]([CH3:28])([CH3:27])[CH3:25])[O:10][N:9]=2)=[CH:4][N:3]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ncc(C=NO)cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(-c2cc(C#C[Si](C)(C)C)on2)cn1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-pyrimidine-5-carbaldehyde oxime (145 gm) in DMF (435 ml) was added N-chlorosuccinamide (169.6 gm) in portions at 30° C. for 0.5 h. As the TLC indicated completion of the reaction, diethyl ether (1450 ml) was added. The reaction mixture was cooled to −5° to 0° C. To a cooled reaction mixture, was added triethylamine (589 ml) followed by trimethylsilylacetylene (450 ml). The mixture was stirred at −5° C. for additional 1 h. The solid separated was filtered at suction. Filtrate was washed with water (300 ml×4) followed by brine solution (500 ml) and organic layer was concentrated under vacuum to provide a solid in 158 gm quantity which was used as it is for further reaction.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])[CH3:3].[H-].[Na+].[CH3:21]I.Cl>O1CCCC1.CN(C)C=O.O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[O:14][CH3:21])[C:8]([OH:10])=[O:9])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc(C(=O)O)cc1C(C)(C)C
Reaction time: 19 h

Procedure:
To 50 g {200 mmol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxy benzoic acid dissolved in 1.1 liters of a 10/1 tetrahydrofuran/dimethylformamide solution were added 24.0 g of a sodium hydride dispersion (60%, by weight, sodium hydride dispersed in mineral oil). The sodium hydride dispersion was added portionwise at a rate such that the reaction solution temperature was kept below 35° C. The resulting solution was stirred for 19 hours and then 28.4 g (220 mmol) of methyl iodide were added. The resulting solution was stirred for 22 hours and then 25 ml of water were added to quench the reaction. Four hundred milliliters of a 1N hydrochloric acid solution were then added in order to acidify the quenched solution. The acidic solution was then concentrated and extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed three times with water and once with a saturated brine solution and then concentrated to dryness to provide residue. This residue was crystallized from a hexane/methylene chloride solution to provide 34.62 of title product m.p. 192°-195° C.
Reaction SMILES: [H-].[Na+].O[C:4]1([CH3:14])[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.[OH2:23]>CN(C=O)C>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([O:23][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:13]=2)[CH:21]=1
Reactant: CC1(O)C=Cc2ccccc2N1
Reactant: O
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)c2ccccc2n1
Reaction time: 0.25 h

Procedure:
36 mg (0.83 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0 10 g (0.68 mmol) 2-hydroxy-2-methylquinoline in 1.5 mL DMF and the mixture was stirred for 15 min. Then 97 mg (0.63 mmol) 4,6-dichloropyrimidine were added and the mixture was stirred overnight at RT. The reaction mixture was mixed with water and left to stand overnight. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [F:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:23]=[CH:24][C:25]([O:33][CH3:34])=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=5)[CH:20]=4)[N:15](S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:23]=[CH:24][C:25]([O:33][CH3:34])=[C:26]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH:27]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4ccc(F)cc4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(CCc5ccc(F)cc5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 41.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(4-fluorophenethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl) methanesulfonamide (25 mg, 0.0379 mmol) was hydrolyzed by lithium hydroxide (15 mg, 0.379 mmol) in THF/methanol/water (2/2/1 ml) to yield 8 mg (40.0% yield) of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 11.7 (s, 1H), 9.034-9.035 (d, 1H), 8.43-8.42 (d, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.69-7.68 (d, 2H), 7.58-7.56 (m, 2H), 7.26-7.18 (m, 3H), 7.11-7.05 (m, 2H), 4.39-4.35 (t, 2H), 3.89 (s, 3H), 3.18-3.13 (t, 2H), 3.00 (s, 3H). MS: m/z=506.5 (M+1), HPLC: 96.65% in method B.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[BrH:10].CS(C)=O>C(O)(=O)C.O>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: Br
Reactant: CCc1ccccc1O
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(Br)ccc1O
Reaction time: 1 h
Yield: 103 %

Procedure:
To a stirred solution of 2-ethylphenol (8.97 g, 73.4 mmol) in acetic acid (100 ml) was added hydrobromic acid (48 wt. % solution in water; 50 ml, 442 mmol), DMSO (50 ml, 705 mmol) dropwise, and the mixture was stirred for 1 hour. The mixture was diluted with water, and the whole was extracted with diethylether. The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo to give title compound (15.2 g, 99% yield). The compound was used for next reaction without purification.