Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][CH:3]=1.[CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>>[CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:13]3=[C:14]4[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]3)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]4=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: O=CN1CCNCC1
Reactant: CC1CCc2c(Cl)ccc3c(=O)c(C(=O)O)cn1c23
Product: CC1CCc2c(N3CCN(C=O)CC3)ccc3c(=O)c(C(=O)O)cn1c23

Procedure:
In an analogous manner as in Example 1, 8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid was reacted with 1-formylpiperazine to form 8-(4-formyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([CH:26]1[CH2:28][O:27]1)[CH2:23][CH2:24][CH3:25]>>[OH:27][CH:26]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:28][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: CCCCC1CO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CCCCC(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 162 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-butyloxirane and conditions outlined in procedure X. M.p.=160-163° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 3.7 (m, 1H), 2.95 (m, 3H), 2.8-2.7 (m, 2H), 2.5-2.35 (m, 3H), 2.15 (d, 2H), 1.95-1.8 (m, 2H), 1.5-1.3 (m, 6H), 0.9 (t, 3H); LCMS: 402 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCC(F)(F)F)nc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1nccc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (20 mg, 0.06 mmol, Step-1 of Example 97, single enantiomer) and isobutyryl chloride (31 mg, 0.29 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH2:5]([C:12]1[C:13]2[CH2:36][NH:35][CH2:34][CH2:33][C:14]=2[N:15]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[N:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[CH2:5]([C:12]1[C:13]2[CH2:36][N:35]([CH2:2][C:3]#[N:4])[CH2:34][CH2:33][C:14]=2[N:15]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[N:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Reactant: N#CCBr
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CN(CC#N)CC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Bromoacetonitrile (0.031 mL, 0.45 mmol) was added to a solution of 4-benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (175 mg, 0.41 mmol, Example 106) and TEA (0.063 mL, 0.45 mmol) in THF (3 mL). The solution was stirred at RT for 2 hours. Solvent was evaporated and the crude product was purified on a prepHPLC yielding 2-(4-benzyl-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)acetonitrile (72.0 mg, 37.7%). MS (ES+) m/z 466.3 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>>[Br:7][C:8]1[CH:17]=[C:16]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(F)cc1Br
Product: COC(=O)c1ccc(N2CCNCC2)cc1Br

Procedure:
This example was prepared by substituting piperazine for EXAMPLE 1B and methyl 2-bromo-4-fluorobenzoate for EXAMPLE 1C in EXAMPLE 1D.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C@H:12]1[O:17][C@@H:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:13][CH:12]([CH3:11])[O:17][CH:16]([CH3:18])[CH2:15]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC1CN(c2ccc(Br)cc2C=O)CC(C)O1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
A mixture of 5-bromo-2-fluorobenzaldehyde (16.0 g, 78.6 mmol), cis-2,6-dimethylmorpholine (9.32 g, 80.9 mmol), and potassium carbonate (15.0 g, 108 mmol) in DMF (75 mL) is heated in a 120° C. oil bath for 14 hours. The mixture is diluted with MTBE (250 mL) and washed with water (4×200 mL). (Ethyl acetate is added as needed to maintain the homogeneity of the organic layer). The organics are filtered through a 1″ plug of silica gel and evaporated to give 21.5 g of brown solid. This material is approximately 90% pure as judged by HPLC and is used without further purification. 1H NMR (DMSO-d6) δ 10.11, 7.78, 7.75, 7.17, 3.77-3.86, 3.12, 2.56, 1.11.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:11]([O:10][C:8](=[O:9])[C:7](=[N+:22]=[N-:23])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl phenylacetate (3.28 g) in acetonitrile (60 mL) is added para-toluenesulfonylazide (4.53 g). The reaction mixture is cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.9 mL) is added dropwise. The reaction mixture is kept at 5° C. overnight. Solvent is removed to dryness and the residue is purified by chromatography (gradient petroleum ether/dichloromethane from 90/10 to 80/20) to give diazophenylacetic acid ethyl ester;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][NH:8][C:9]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])[N:15]=[C:14]3[C:10]=2[NH:11][C:12]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[N:13]3)=[CH:5][CH:4]=1.[CH2:30](Br)[CH:31]=[CH2:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])[N:15]=[C:14]3[C:10]=2[N:11]=[C:12]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[N:13]3[CH:31]([CH3:32])[CH3:30])=[CH:28][CH:29]=1
Reactant: C=CCBr
Reactant: COc1ccc(CNc2nc(NCCCO)nc3nc(NCCCO)[nH]c23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(NCCCO)nc3c2nc(NCCCO)n3C(C)C)cc1
Yield: 55 %

Procedure:
6-(4-Methoxybenzylamino)-2,8-bis(3-hydroxypropylamino)purine (0.07 mmol) was stirred in 2 mL dimethylformamide with 0.14 mmol of allylbromide and with 0.36 mmol of dry potassium carbonate at ambient temperature (6 hours). The solvent was evaporated to dryness and the rest extracted between ethylacetate—water. The organic layer was dried, ethylacetate was evaporated and the rest purified by column chromatograpy (silica gel, chloroform). Yield 55%. MS-ESI(+)m/z 441.4 [M+H]+
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[C:6]([S:10]([NH2:12])=[O:11])([CH3:9])([CH3:8])[CH3:7]>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:1]1(=[N:12][S:10]([C:6]([CH3:9])([CH3:8])[CH3:7])=[O:11])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CCC1
Reaction time: 0.17 h
Yield: 77 %

Procedure:
A mixture of titanium (IV) ethoxide (22.4 mL, 107 mmol) and cyclobutanone (5.37 mL, 71.0 mmoL) in tetrahydrofuran (120 mL) was stirred for 10 minutes. Tert-butanesulfinamide (7.17 g, 59.0 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulphate and concentrated to give N-cyclobutylidene-2-methylpropane-2-sulfinamide (9.51 g, 77%) as a pale yellow oil which was used directly without purification.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].II.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1
Reactant: BrBr
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a 100 mL 3-neck round bottom equipped with a dropping funnel was added trichloroacetyl pyrrole (50 g, 236.4 mmol) and CCl4 (1.0 L). After trichloroacetyl pyrrole was dissolved, the reaction was cooled to 0° C. and iodine (0.176 g) was added to the reaction. At this time, a solution of bromine (12 mL) in CCl4 (100 mL) was added dropwise very slowly to the reaction through a dropping funnel over 20 minutes and the resulting mixture was stirred at 0° C. for additional 20 minutes. The resulting mixture was transferred into a separatory funnel and washed with 10% Na2S2O3 solution, saturated NaHCO3 solution and brine (2×). The organic layer was dried and concentrated to give 50 g (60%) of the title compound as a white solid. LCMS (condition A): m/z=287.8, 289.8, 290.8 −ve. H1 NMR (400 MHz, CDCl3) δ ppm: 12.8 (1H, br.s), 7.56 (1H, m), 7.33 (1H, m).
Reaction SMILES: COC([CH:5]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:22])=O.S(=O)(=O)(O)O>[OH-].[Na+].C(O)C.C1COCC1>[C:6]1(=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:5]1
Reactant: COC(=O)C1CCCCCCC=CCCCCCCCC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1CCCCCCCC=CCCCCCCC1
Temperature: 80 °C
Yield: 94.5 %

Procedure:
2-Methoxycarbonyl-9-cycloheptadecenone (92 mg, 0.30 mmol) was dissolved in a mixed solvent of 5% aqueous NaOH/ethanol/THF (2.5:5.0:2.5, vol./vol./vol.) and the solution was refluxed at 80° C. for 5 hours. After cooling to 0° C., the reaction solution was rendered slightly acidic using 10% sulfuric acid aqueous solution and the whole was further refluxed for 10 minutes. After the evaporation of the solvent under reduced pressure, the residue was extracted with ether. The organic layer was washed with saturated sodium hydrogen carbonate aqueous solution, water, and saturated brine, and then dried over anhydrous sodium sulfate. After the evaporation of the solvent under reduced pressure, the crude product was purified by silica gel chromatography (hexane/ethyl acetate=40/1) to obtain the aimed product (71 mg, 95%)
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][S:5][N:4]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1>>[S:5]1[N:6]=[CH:7][C:3]([CH2:2][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=2)=[N:4]1
Reactant: BrCc1cnsn1
Reactant: CC(=O)Cc1ccc(O)cc1
Product: CC(=O)Cc1ccc(OCc2cnsn2)cc1

Procedure:
Prepared from 3-bromomethyl-1,2,5-thiadiazole and 4-hydroxyphenylacetone by the method of Example 1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7].[Mg].[CH3:9][C:10]1([CH3:24])[CH2:23][N:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21](=[O:22])[C:13]2=[N:12][CH2:11]1.[Cl-].[NH4+]>C(OCC)C.ClCCCl>[CH3:9][C:10]1([CH3:24])[CH2:23][N:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]([OH:22])([CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7])[C:13]2=[N:12][CH2:11]1
Reactant: CC1(C)CN=C2C(=O)c3ccccc3N2C1
Reactant: COCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCOCC
Product: COCCCCC1(O)C2=NCC(C)(C)CN2c2ccccc21
Reaction time: 0.75 h

Procedure:
A solution of 1-bromo-4-methoxybutane (6.26 g) in diethyl ether (23 ml) was added dropwise to stirred magnesium turnings (0.9 g) under nitrogen, at a rate sufficient to maintain reflux. The mixture was stirred for a further 45 min., then a solution of 3,4-dihydro-3,3-dimethylpyrimido[1,2-a]indole-10(2H)-one (1.6 g) in 1,2-dichloroethane (75 ml) was added dropwise. The mixture was stirred for 30 min., then poured into aqueous ammonium chloride solution and extracted with chloroform (2×100 ml). The chloroform extracts were combined, dried (MgSO4) and evaporated under reduced pressure giving an orange solid. Trituration from ethyl acetate, followed by recrystallisation from ethyl acetate gave the title compound (1.2 g(. Addition of ethereal hydrogen chloride to a solution of the free base in methanol, followed by evaporation of the solvents and crystallisation of the resulting solid from propan-2-ol gave the hydrochloride salt (0.6 g), m.p. 188°-190°.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]3[N:15]=[C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][N:17]4[C:18](=[O:21])[C:19]=3[CH3:20])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:31].[CH3:20][C:19]1[C:18](=[O:21])[N:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=[N:15][C:14]=1[O:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=2)=[CH:9][CH:10]=1
Reactant: Cc1c(OCc2ccc(C(=O)c3ccc(O)cc3)cc2)nc2ccccn2c1=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(OCCN4CCOCC4)cc3)cc2)nc2ccccn2c1=O
Yield: 16.6 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (104 mg), 4-(2-chloroethyl)morpholine hydrochloride (90 mg) and potassium carbonate (179 mg) in DMF (7 ml) was stirred at 100° C. for 20 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. Then, hydrogen chloride-ethyl acetate was added and the precipitated hydrochloride was collected by filtration and dried to provide the title compound as colorless solid (24 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][N:14]=[C:15]([C:20](=[O:24])[CH2:21][O:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17].[CH:25](OC(OC(C)C)N(C)C)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[N:13]1[CH:25]=[C:21]([O:22][CH3:23])[C:20](=[O:24])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:14]1
Reactant: COCC(=O)C(=NNc1ccc(OC(F)(F)F)cc1F)C(=O)OC
Reactant: CC(C)OC(OC(C)C)N(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1nn(-c2ccc(OC(F)(F)F)cc2F)cc(OC)c1=O
Yield: 85.3 %

Procedure:
A solution of methyl 2-{[2-fluoro-4-(trifluoromethoxy)phenyl]hydrazono}-4-methoxy-3-oxobutanoate (3.8 g, 11 mmol) and N,N-dimethylformamide diisopropyl acetal (9.5 mL, 54 mmol) in toluene (60 mL) was refluxed for 5 h. The mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (10/90-100/0 AcOEt/hexane) to give the title compound (3.4 g, 86% yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.91 (3H, s), 3.97 (3H, s), 7.17-7.25 (2H, m), 7.68-7.76 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:12][CH2:11][C:9]1[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=[C:2]([Cl:1])[CH:10]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(CO)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(COS(C)(=O)=O)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methanol (2.5 g, 8 mmol) and triethylamine (3.34 mL, 24 mmol) in dichloromethane (120 mL) at 0° C. was added methanesulfonyl chloride (1.25 mL, 16 mmol). The reaction was stirred at 0° C. for 1 h. The reaction was quenched by addition of water, stirred 5 min, and poured into water. The layers were separated and the organics washed with brine, dried over magnesium sulfate, and concentrated to give 3.25 g (quant.). 1H-NMR (CDCl3, 500 MHz) δ 8.09 (s, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.31 (d, J=0.9 Hz, 1H), 5.68 (s, 2H), 5.59 (s, 2H), 3.60 (t, J=8.2 Hz, 2H), 3.06 (s, 3H), 0.91 (t, J=8.2 Hz, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 145.4, 127.5, 127.4, 125.0, 123.0, 122.8, 120.5, 82.1, 67.8, 67.4, 38.0, 17.9, −1.4. Mass spec.: 391.14 (MH)+.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C=O.[C:21](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:12]([O:11][C:9]([N:4]1[CH2:3][CH:2]([CH3:1])[N:7]([CH3:21])[CH:6]([CH3:8])[CH2:5]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1CN(C(=O)OCc2ccccc2)CC(C)N1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC1CN(C(=O)OCc2ccccc2)CC(C)N1C
Reaction time: 0.17 h

Procedure:
Benzyl 3,5-dimethylpiperazine-1-carboxylate (1 eq, 2.04 mmol, 0.5 g) and formaldehyde (37% in H2O, 5 eq, 10.07 mmol, 0.277 ml) are dissolved in MeOH (10 ml). After 10 mins at room temperature, acetic acid (5 eq, 10.07 mmol, 0.576 ml) and sodium triacetoxyborohydride (5 eq, 10.07 mmol, 2.13 g) are added and the reaction mixture stirred overnight. The reaction is quenched with 5M HCl (15 ml) and the solvent evaporated under vacuo. The residue is taken to pH 13 by addition of sodium hydroxide (4M) and extracted with EtOAc. This organic portion is washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1>COCCOC.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:30][C:28]1[CH:29]=[C:24]([C:17]2[CH:18]=[CH:19][C:14]([O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:15][CH:16]=2)[C:25]([NH2:31])=[N:26][CH:27]=1
Reactant: Nc1ncc(F)cc1Br
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(F)cc1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 3-bromo-5-fluoropyridin-2-amine (110 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (132 mg) as a pale yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]1[N:4]=[C:5]2[C:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[C:2]([C:3]1[N:4]=[C:5]2[C:11]([C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)(=[O:1])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(C(O)c3ccccc3)nc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(C(=O)c3ccccc3)nc12

Procedure:
1-[2-(Hydroxy-phenyl-methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was treated with Dess-Martin periodinane, following general procedures described in these Examples. MP=190-192, (M+H)+=308.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:15](=[O:16])[NH:14][C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1.[CH2:17](Br)[CH3:18]>CN(C)C=O>[Br:3][C:4]1[C:15](=[O:16])[N:14]([CH2:17][CH3:18])[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1
Reactant: CSc1ncc2cc(Br)c(=O)[nH]c2n1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(Br)cc2cnc(SC)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a suspension of NaH (60%, 0.15 g, 3.75 mmol) in anhydrous dimethylformamide (10 mL) was added 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.68 g, 2.50 mmol) at room temperature and the reaction was stirred at 50° C. for 0.5 h. The reaction mixture was cooled down to room temperature and ethyl bromide (0.22 mL, 0.32 g, 2.93 mmol) was added and stirred at 50° C. for 1.5 h. After completion, the mixture was poured onto ice water (10 g), and the white precipitate was filtered off to give 6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.57 g, 1.90 mmol, 76%). ESMS m/z 300 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:27](OC)([O:30]C)[O:28]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:27]([OH:30])[OH:28])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=2[O:9][CH2:8]1
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3-dimethyl-7-t-butyl-2,3-dihydro-benzofuran (1.42 g, 7 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (8.25 mL, 14 mmol) and trimethyl borate (1.5 mL, 14 mmol), the title compound was obtained as a foam that was used as such for the next step without purification and characterization. 5-Bromo-3,3-dimethyl-7-t-butyl-2,3-dihydro-benzofuran can be prepared as described by Janusz et al. in J. Med. Chem. 1998, 41, 1124-1137.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[C:29]([S:32](Cl)(=[O:34])=[O:33])[C:28]([CH3:36])=[N:27]1.C(N(CC)CC)C>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:20][CH2:21][N:22]([S:32]([C:29]3[C:28]([CH3:36])=[N:27][N:26]([CH3:25])[C:30]=3[CH3:31])(=[O:33])=[O:34])[CH2:23][CH2:24]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCNCC3)c[nH]c12
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(C)c1S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1

Procedure:
Following the general procedure in example 267, 5-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (24.4 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (9 mg, 18%).