Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[O:32]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH:37][C@H:34]5[CH2:35][CH2:36][O:32][CH2:33]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: N[C@H]1CCOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)N[C@H]5CCOC5)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), (S)-tetrahydrofuran-3-amine hydrochloride (0.161 g, 1.3 mmol), DIEA (0.26 mL, 1.5 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to produce a crude yellow solid, which was washed with methanol to produce a purified product (0.363 g) in 74.1% yield.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:15]3[CH2:20][CH2:19][CH2:18][C:17](=O)[CH2:16]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.Cl.[CH2:23]([NH2:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([NH:29][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CCCCCCN
Reactant: O=C1CCCN(S(=O)(=O)c2cccc3c(Cl)nccc23)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCCNC1CCCN(S(=O)(=O)c2cccc3c(Cl)nccc23)C1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To 50 ml of methanol were added 2.47 g of the thus obtained 1-(1-chloro-5-isoquinolinesulfonyl)-3-piperidone, 1.11 g of n-hexylamine hydrochloride and 0.50 g of sodium cyanoborohydride, followed by stirring at 20° C. for 15 hours. The methanol was removed under reduced pressure, and 50 ml of chloroform was added to the resultant product. Then, the mixture was washed twice with 50 ml each of water and then washed once with 50 ml of a 50% aqueous sodium hydrogencarbonate solution, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, 100 g; solvent: chloroform) to obtain 2.54 g of 1-(1-chloro-5-isoquinolinesulfonyl)-3-hexylaminopiperidine [Compound (98)]. Compound (98) was analyzed to give the following data.
Reaction SMILES: N1C=CC=CC=1S(O)(=O)=O.[CH:11]([N:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O.C(N(CC)CC)C>[CH:11]([N:24]1[CH2:27][C:26](=[O:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=S(=O)(O)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 60 %

Procedure:
Under cooling with ice, pyridinesulfonic acid (19.7 g) in dimethyl sulfoxide (84 mL) was added dropwise to 1-benzhydrylazetidin-3-ol (4.79 g) in triethylamine (27.9 mL), and the resultant mixture was stirred at 50° C. for 40 minutes. The reaction mixture was partitioned between ice-water and ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid (2.85 g, 60%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCCC1.O>C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>[CH:12](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)c1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Yield: 87.7 %

Procedure:
A mixture containing 3.0 mL (19.8 mmoles) of diethyl malonate, 2.0 mL (19.6 mmoles) of benzaldehyde, 0.10 mL of piperidine, and 65 mg of benzoic acid in 35 mL of benzene was heated at reflux for 6 hours with continuous azeotropic removal of water by means of a Dean-Stark trap. Isolation of the product in the manner described in the procedure of Example I, followed by fractional distillation, afforded 4.27 g (88% yield) of diester 8: bp 105°-140° C. (bath temperature, 0.10 mm). Subsequent treatment of diester 8 with 2-nitropropane and sodium ethoxide in ethanol at reflux, as described for the corresponding cyanoester 1 in Example VIII, failed to yield a cyclopropanoid product.
Reaction SMILES: Br[C:2]1[C:3]([CH2:9][N:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.O>CN(C=O)C.[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:12])[N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:9][C:3]=2[N:4]=1
Reactant: COc1ccc(CN(Cc2nc(F)ccc2Br)C(=O)Nc2ccccc2)cc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3nc(F)ccc3N(c3ccccc3)C2=O)cc1
Temperature: 150 °C
Yield: 55 %

Procedure:
To a solution of (3-bromo-6-fluoro-pyridin-2-ylmethyl)-(4-methoxy-benzyl)-3-phenyl-urea (644 mg, 1.5 mmol, 1.0 equiv) and N,N-diisopropylethylamine (500 μL, 2.9 mmol, 2.0 equiv) in DMF (15 mL) was added CuI (331 mg, 1.7 mmol, 1.2 equiv) and the reaction mixture was heated at 150° C. for 5 h. The reaction mixture was cooled, H2O was added and the product was extracted with EtOAc. The organic phase was washed with dilute NH4OH, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-50%) to afford 6-fluoro-3-(4-methoxy-benzyl)-1-phenyl-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one (300 mg). MS: [M+H]+=364.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH2:27])[CH2:24][CH2:23][CH2:22]2.[NH:28]1[CH:32]=[C:31]([CH:33]=O)[N:30]=[N:29]1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH:27][C:8]1[CH:7]=[CH:6][C:5]3[C:4]([NH:1][CH2:33][C:31]4[N:30]=[N:29][NH:28][CH:32]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=1)[CH2:24][CH2:23][CH2:22]2
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: COc1cccc2c1C(N)CCC2
Reactant: O=Cc1c[nH]nn1
Product: COc1cccc2c1C(Nc1ccc3c(NCc4c[nH]nn4)cccc3n1)CCC2

Procedure:
The title compound, MS: m/e=401.5 (M+H+), was prepared in accordance with the general method of example 43 from 5-nitro-2-chloroquinoline, rac-8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine (CAS 535935-61-6) and 1H-1,2,3-triazole-4-carbaldehyde.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][F:5].[CH2:6]([O:13][C:14](=[O:43])[C@@H:15]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)(=[O:35])=[O:34])=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:6]([O:13][C:14](=[O:43])[C@@H:15]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)(=[O:35])=[O:34])=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][F:5])=[CH:19][CH:18]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: FCCCBr
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccc(OCCCF)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
3-Bromo-1-fluoro propane (1.6 g, 11 mmol) was added to a mixture of (S)-2-{[(S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (compound 17c) (2.0 g, 3.7 mmol) and cesium carbonate (3.6 g, 11 mmol) in DMF (60 mL). The suspension was stirred overnight at room temperature. The reaction mixture was diluted in ethyl acetate and washed with water, dried over magnesium sulfate and concentrated. The resulting oil was chromatographed (dichloromethane/methanol, 9/1) on silica gel to produce 1.89 g (85.1%) of the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.FC(F)(F)[C:29]1[CH:30]=[C:31]([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)[CH:32]=[CH:33][CH:34]=1.C1COCC1.C(O)(=O)/C=C/C(O)=O>CN(C=O)C.C(O)C>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:38]1[CH2:37][CH:36]=[C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:29][CH:30]=2)[CH2:40][CH2:39]1)[O:14]3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2ccccc2)CC1)CO3
Temperature: 25 °C
Yield: 20.1 %

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.40 g, 1.1 mmole) and 4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (0.35 g, 1.54 mmole) were combined in 5 mL of DMF and 5 ml of THF under nitrogen. This solution was refluxed under nitrogen for overnight. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute the (S)-enantiomer of the title compound. This was recrystallized from ethanol with the addition of one equivalent of fumaric acid to give 80 mg of white solid, m.p. 170-173° C.
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].[NH2:10][C:11]1[CH:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:14](Br)=[CH:13][N:12]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>CO.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>[NH2:10][C:11]1[CH:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:14]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[CH:13][N:12]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(N)ncc2Br)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: CO
Solvent: CC#N
Product: COc1ccc(-c2cnc(N)cc2NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
Acetonitrile (1212 μL) and 0.5M sodium carbonate solution (0.36 mL, 1.5 eq) were added to tert-butyl 4-(2-amino-5-bromopyridin-4-ylamino)piperidine-1-carboxylate (45 mg, 0.121 mmol), 4-methoxyphenylboronic acid (27.6 mg, 0.182 mmol), and tetrakis(triphenylphosphine)palladium(0) (7.00 mg, 6.06 μmol) in a microwave vial (0.5 mL). The capped vial was heated to 150° C. by microwave irradiation for 20 min. After cooling the solution was diluted with MeOH and purified by ion exchange on SCX-II acidic resin (2 g) column, eluting with MeOH then 2M ammonia in MeOH. The basic fractions were combined and concentrated. The crude product was dissolved in dichloromethane and loaded onto a Biotage SNAP silica column (10 g) which was eluted with a gradient of MeOH/NH3 (99/1) in dichloromethane to give tert-butyl 4-(2-amino-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate (19 mg, 0.048 mmol, 39%) as a colourless foam.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>CN(C=O)C>[CH3:15][O:16][C:17]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([O:21][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20]
Reactant: BrCc1ccccc1
Reactant: COc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C(=O)OCc2ccccc2)cccc1[N+](=O)[O-]
Reaction time: 1.17 h

Procedure:
At room temperature, benzyl bromide (8.85 mL) and potassium carbonate (10.3 g) were added to a DMF (150 mL) solution of 2-methoxy-3-nitrobenzoic acid (9.80 g), followed by stirring for 70 minutes. The insoluble matter was separated by filtration, followed by evaporation under reduced pressure. This was subjected to liquid-liquid separation with ethyl acetate, aqueous sodium hydrogencarbonate solution, and hexane added thereto. The organic layer was washed with water and saturated brine in that order, dried, and then evaporated under reduced pressure to obtain benzyl 2-methoxy-3-nitrobenzoate (14.3 g).
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=2)[CH:9]=1)[C:4](=[O:7])[CH2:5][CH3:6])[CH3:2].[CH3:21][NH:22][C:23](=S)[NH:24][NH2:25]>C(O)C>[CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]3[N:16]([C:23]([NH:22][CH3:21])=[N:24][N:25]=3)[N:15]=2)[CH:9]=1)[C:4](=[O:7])[CH2:5][CH3:6])[CH3:2]
Reactant: CCC(=O)N(CC)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CNC(=S)NN
Solvent: CCO
Product: CCC(=O)N(CC)c1cccc(-c2ccc3nnc(NC)n3n2)c1
Yield: 8.9 %

Procedure:
A solution of 5.0 g N-ethyl-N[3-(6-chloro-3-pyridazinyl)phenyl]propanamide and 3.8 g of 4-methylthiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was then treated and the product chromatographed as described for Example 70. Recrystallization of the product from acetone-hexane afforded 0.5 g orange crystals, mp 172°-173° C.
Reaction SMILES: [CH3:1]C1C=CC=C(C)C=1C(O)=O.BrBr.[Br:14][C:15]1[C:16]([CH3:25])=[C:17]([C:21]([CH3:24])=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].CI>C(O)(=O)C>[Br:14][C:15]1[C:16]([CH3:25])=[C:17]([C:21]([CH3:24])=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].[Br:14][C:15]1[C:16]([CH3:25])=[C:17]([C:21]([CH3:24])=[CH:22][CH:23]=1)[C:18]([O:20][CH3:1])=[O:19]
Reactant: Cc1cccc(C)c1C(=O)O
Agent: BrBr
Agent: Cc1ccc(Br)c(C)c1C(=O)O
Solvent: CC(=O)O
Solvent: CI
Product: COC(=O)c1c(C)ccc(Br)c1C

Procedure:
3-Bromo-2,6-dimethylbenzoic acid was prepared from 2,6-dimethylbenzoic acid by treatment with bromine in acetic acid; see Org. Synth. Coll., Vol. 3, 138 (1944). 3-Bromo-2,6-dimethylbenzoic acid was esterified with methyl iodide as described in Tet. Letters, 689 (1973) to give methyl 3-bromo-2,6-dimethylbenzoate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8](C3C=CC(F)=CC=3)[C:6]=2[N:7]=1.FC(F)(F)C1CCNC1>>[N:7]1[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=2[CH:4]=[N:3][CH:2]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Agent: FC(F)(F)C1CCNC1
Product: c1ncc2c(n1)CCC2

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 3-trifluoromethylpyrrolidine to afford 2-chloro-7-(4-fluorophenyl)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation Ht) as a mixture of 4 diasteriomers. LC-MS (M+H)+=386.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.05-7.11 (2 H, m), 6.96 (2 H, t, J=8.70 Hz), 4.14-4.20 (1 H, m), 3.89-4.02 (2 H, m), 3.75-3.86 (2 H, m), 3.17-3.28 (1 H, m), 3.06-3.16 (1 H, m), 2.99 (1 H, dq, J=15.95, 8.01 Hz), 2.50-2.61 (1 H, m), 2.13-2.30 (2 H, m), 1.95-2.06 (1 H, m)
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([NH:14][C:15]1[CH:46]=[CH:45][C:18]([C:19]([N:21]([CH3:44])[C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])=[O:20])=[CH:17][C:16]=1[O:47][CH3:48])=[O:13])[CH:8]=[CH:7][CH:6]=2)=O.Cl.[NH2:50][OH:51]>N1C=CC=CC=1>[OH:51][N:50]=[CH:1][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([NH:14][C:15]1[CH:46]=[CH:45][C:18]([C:19]([N:21]([CH3:44])[C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])=[O:20])=[CH:17][C:16]=1[O:47][CH3:48])=[O:13])[CH:8]=[CH:7][CH:6]=2
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C=O)cc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C=NO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 4-[(2-formylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in pyridine (4.0 ml) was added hydroxylamine hydrochloride (21.3 mg) and the solution was stirred at ambient temperature for 1 hour. The resulting solution was concentrated in vacuo and the residue was diluted with chloroform. The organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 4-[(2-hydroxyiminomethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (203 mg).
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])C.ClC1[N:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[S:34][C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=3)=[CH:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1>C1COCC1>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:6]1[CH:17]=[CH:18][C:19]2[C:24](=[N:23][CH:22]=[CH:21][C:20]=2[NH:26][C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=2[S:34][C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)[N:25]=1)[CH3:13])[CH3:12]
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a slurry of sodium hydride (95%, 0.025 g, 1.0 mmol) in 5 mL anhydrous THF at 0° C. under an atmosphere of N2 was added 2-methyl-malonic acid diethyl ester (0.174 g, 1.0 mmol) dropwise. The mixture was stirred for 30 minutes at ambient temperature, treated with the product from Example 24a (0.047 g, 1.0 mmol), microwave at 120° C. for 1 hour, cooled, partitioned between ethyl acetate and water and neutralized with 1M HCl. The aqueous layer was extracted by ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound. The residue was purified by chromatography on silica eluting with 1% methanol in dichloromethane to give the title compound (0.031 g, 62%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.14 (t, J=7.17 Hz, 3 H) 1.52 (d, J=7.35 Hz, 3 H) 2.04 (s, 3 H) 2.30 (s, 3 H) 4.10 (m, 3 H) 6.17 (s, br, 1 H) 7.04 (m, 3 H) 7.26 (d, J=8.82 Hz, 2 H) 7.48 (d, J=7.35 Hz, 1 H) 7.57 (d, J=8.46 Hz, 2 H) 8.45 (d, J=8.46 Hz, 1 H) 8.78 (d, J=8.82 Hz, 1 H) 9.11 (s, 1 H) 10.05 (s, 1H); (ESI+) m/z 501 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2Cl)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([NH2:34])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CC(O)(C)C.ClCCCl>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:34][C:23]1[CH:24]=[CH:25][C:26]([O:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:21]([CH3:20])[CH:22]=1)=[O:4]
Reactant: O=C(CCl)NCC#Cc1ccc2ncnc(Cl)c2c1
Reactant: Cc1cc(N)ccc1Oc1cccnc1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CCl)cc23)ccc1Oc1cccnc1
Yield: 88.8 %

Procedure:
A mixture of 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide (0.90 g, 3.05 mmol) and 3-Methyl-4-(pyridin-3-yloxy)-phenylamine (0.61 g, 3.05 mmol) in tBuOH/DCE (5.0/5.0 mL) was refluxed under nitrogen for 40 minutes and concentrated. The residue was dissolved in MeOH (2.0 mL) and added to EtOAc with vigorous stirring to precipitate the HCI salt product as tan solid which was collected by vacuum-filtration, rinsed with EtOAc, and further dried to give 1.24 g (82%) of 2-Chloro-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide: 1H NMR (CD3OD) δ 2.27 (s, 3H), 4.09 (s, 2H), 4.29 (s, 2H), 7.07 (d, 1H), 7.51 (m, 2H), 7.60 (d, 1H), 7.70 (s, 1H), 7.78 (d, 1H), 8.05 (d, 1H), 8.32 (m, 2H), 8.67 (s, 1H), 8.75 (s, 1H); MS m/z (MH+) 458.0.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:13]2=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]2[CH:11]=[CH:10][CH:9]=1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.O>COCCOC.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>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([C:8]2[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: O=S1(=O)CCN2C=CC=C(Br)C2=N1
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: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3)C2=N1
Temperature: 100 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (32.9 mg) was added to a mixture of 2M aqueous sodium carbonate solution (0.428 mL), 9-bromo-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) and biphenyl-4-ylboronic acid (135 mg) in 1,2-dimethoxyethane (5.701 ml). The reaction mixture was stirred under a nitrogen atmosphere at 100° C. overnight, added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, then ethyl acetate/methanol) to give the title compound (44.5 mg) as a pale-brown solid.