Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:15]([NH:28][C:29](=[O:37])[N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH:15]([NH:28][C:29](=[O:37])[N:30]([C@@H:31]1[CH2:35][CH2:34][N:33]([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:32]1)[CH3:36])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C(=O)NC(c1ccccc1)c1ccccc1)C1CCNC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(C(=O)NC(c1ccccc1)c1ccccc1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of bromodiphenylmethane (0.43 g, 1.75 mmol) in butanone (10 ml) was added 3-benzhydryl-1-methyl-1-pyrrolidin-3-yl-urea(0.65 g, 2.1 mmol), K2CO3 (0.24, 1.75 mmol) and KI (0.29 g, 1.75 mmol). The mixture was heated under reflux for 18 hours, then filtered and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and washed with water (10 ml). Drying over MgSO4 and removal of solvent under reduced pressure followed by column chromatography using Hex:EtOAc (1:1) gives the desired product.
Reaction SMILES: [N:1]#[C:2][NH2:3].C(OC(=O)[N:10]([CH2:23][CH3:24])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)(C)(C)C.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35](=[O:38])[CH2:36]Br)=[CH:34][C:29]=2[O:28][CH2:27]1>>[NH2:1][C:2]1[N:3]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][NH:10][CH2:23][CH3:24])=[CH:19][CH:18]=2)[S:22][C:36]=1[C:35]([C:33]1[CH:32]=[CH:31][C:30]2[O:26][CH2:27][O:28][C:29]=2[CH:34]=1)=[O:38]
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Reactant: N#CN
Reactant: CCN(CCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Product: CCNCCOc1ccc(Nc2nc(N)c(C(=O)c3ccc4c(c3)OCO4)s2)cc1

Procedure:
This compound was prepared from cyanamide, ethyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-carbamic acid tert-butyl ester of Example 129D and 1-benzo[1,3]dioxol-5-yl-2-bromoethanone (Example 132) following a procedure similar to Example 130. The crude product was purified by HPLC using a Waters Symmetry C-18 21.2×75 mm column with the following gradient: A (0.05% trifluoroacetic acid in water), B (0.035% trifluoroacetic acid in acetonitrile, A to B gradient (0 to 50% over 7 minutes) flow rate: 20 mL/minute. The recovered product was dissolved in ethyl acetate, washed with 0.05N aqueous sodium hydroxide, and then with water. The ethyl acetate was dried (Na2SO4), concentrated, and the resulting residue triturated with ether to yield the product. Mass spectrum (ES) MH+=427.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:44][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyclohexylamine according to conditions described in general procedure C. Mp: 135-136° C.; 1H NMR (400 MHz, CDCl3) δ 1.10-1.25 (m, 6 H), 1.58-1.64 (m, 4 H), 1.19 (bs, 1 H), 3.27 (s, 4 H), 3.87-3.89 (m, 4 H), 4.90 (s, 1 H), 6.05 (s, 1 H), 6.78 (d, J=11.3 Hz, 1 H), 7.07 (d, J=7.8 Hz, 1 H), 7.26 (s, 1 H), 7.31-7.33 (m, 2 H), 7.51-7.61 (m, 2 H), 7.90 (d, J=8.6 Hz, 1 H), 7.97-8.00 (m, 2 H), 8.07 (s, 1 H), 8.12 (s, 1 H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH:10]([CH3:28])[CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[N:43]([C:46]1[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:49]=[C:48]([C:56]([F:59])([F:58])[F:57])[CH:47]=1)=C=O>ClCCl>[F:53][C:52]([F:54])([F:55])[C:50]1[CH:51]=[C:46]([NH:43][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:18][CH:17]=[CH:16][N:15]=3)[CH:10]([CH3:28])[CH2:9]2)=[O:7])[CH:47]=[C:48]([C:56]([F:57])([F:59])[F:58])[CH:49]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1OCc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCN1c1nccnc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
2-Methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (103 mgs, 0.27 mmol) was dissolved in dichloromethane (1.5 mL) to which was added TFA (2.0 mL) and the mixture stirred at room temperature for 1 hr until Boc removal was complete. The reaction mixture was concentrated in vacuo and redissolved in dichloromethane (1.0 mL) to which was added triethylamine (0.2 mL, 1.43 mmol) and 1-isocyanato-3,5-bis-trifluoromethyl-benzene (0.055 ml, 0.32 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 98.9 mgs (69%) of 2-methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide as a white solid after lyophilization from H2O—AcCN. 1H NMR (CDCl3) 8.77 (d, 2H), 7.94 (s, 2H), 7.82 (d, 1H), 7.71 (d, 2H), 7.52 (d, 1H), 7.49 (s, 1H), 7.23 (s, 1H), 5.62 (s, 2H), 4.60 (m, 1H), 4.01 (m, 1H), 3.97-3.86 (m, 2H), 3.52-3.45 (m, 2H), 3.34 (m, 1H), 1.26 (d, 3H) ppm. LC-MS (MH+)=541.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([NH:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20])=[C:13]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([CH3:32])=[C:11]([CH3:33])[N:10]=1>C(O)C>[CH2:17]([C:16]1[N:22]([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[C:12]([CH3:32])=[C:11]([CH3:33])[N:10]=[C:9]([Cl:8])[C:14]=2[N:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(=O)Nc1c(Cl)nc(C)c(C)c1NCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCc1nc2c(Cl)nc(C)c(C)c2n1CCOc1ccccc1

Procedure:
Triethylamine (1.93 ml), anhydrous ethanol (35 ml), and N-{2-chloro-5,6-dimethyl-4-[(2-phenoxyethyl)amino]pyridin-3-yl}pentanamide (1.32 g) from Part A were combined and heated to reflux for 24 hours. The reaction stalled, so the mixture was cooled and the solvent was removed under reduced pressure. Pyridine (75 ml) and an equivalent of pyridine HCl was added and the reaction mixture was heated to reflux for 16 hours. TLC analysis indicated that the reaction was complete. The reaction was allowed to cool and the solvent was removed under reduced pressure. The resulting product was dissolved in ethyl acetate and washed 4 times with water (150 ml each) to remove the pyridine HCl. The organic layer was dried with magnesium sulfate and the solvent was removed under reduced pressure. NMR analysis of the dried brown solid indicated sufficient purity for use of the product in the next step.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH3:29])=O)(=O)OC.O.[NH2:31][NH2:32]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:31]=[N:32][C:3]3[C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]([C:4]=3[CH:19]=2)[CH2:6][CH2:7]4)=[C:23]([CH3:29])[CH:24]=1
Reactant: COP(=O)(CC(=O)c1ccc(Cl)cc1C)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: NN
Solvent: O
Product: Cc1cc(Cl)ccc1-c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
yellow solid. MS (EI): 312.2 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo [2.2.1]heptane-2,3-dione, [2-(4-Chloro-2-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[N+:13]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[C:7]=1[NH:1][CH2:2][CH2:3][CH2:4][OH:5])([O-:15])=[O:14]
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
A mixture of 3-amino-1-propanol (6.77 mL, 89.0 mmol), 2-chloro-1,3-dinitrobenzene (15.0 g, 74.1 mmol), triethylamine (12.4 mL, 89.0 mmol) and tetrahydrofuran (370 mL) was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a solid (17.7 g, 73.3 mmol, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10](I)[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:10][CH3:11])[CH:7]=1
Reactant: CCI
Reactant: Cc1cc(Br)c[nH]c1=O
Product: CCn1cc(Br)cc(C)c1=O

Procedure:
5-Bromo-1-ethyl-3-methylpyridin-2(1H)-one was prepared by alkylation of 5-bromo-3-methylpyridin-2(1H)-one with ethyl iodide following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]=[S:24]1(=[O:49])[C:29]2[CH:30]=[C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43](O)=[O:44])=[CH:37][CH:36]=3)[CH:32]=[CH:33][C:28]=2[N:27]2[CH2:46][CH2:47][CH2:48][C:26]2=[N:25]1.C(N(C(C)C)CC)(C)C.N.Cl>C(Cl)Cl.CCOC(C)=O>[O:23]=[S:24]1(=[O:49])[C:29]2[CH:30]=[C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([NH2:2])=[O:44])=[CH:37][CH:36]=3)[CH:32]=[CH:33][C:28]=2[N:27]2[CH2:46][CH2:47][CH2:48][C:26]2=[N:25]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)CCc1ccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)cc1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CCc1ccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
415 mg (1.30 mmol) of TBTU are added to a suspension (500 mg, 1.30 mmol) of the compound obtained in Step B of Example 2 in 25 ml of CH2Cl2. The suspension is stirred at ambient temperature for 10 minutes and 293 μl (1.68 mmol) of diisopropylethylamine are added. The reaction mixture becomes a solution and stirring is continued for 10 minutes. The solution is then saturated with ammonia gas and stirring is continued for 30 minutes. Thin-layer chromatography (AcOEt) indicates that all the starting material has disappeared. The reaction mixture is then acidified by adding 1N HCl; the organic phase is decanted off, washed (water and then saturated NaCl solution), dried (MgSO4) and evaporated. The residue is triturated in Et2O and the white solid formed is filtered off to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:22]3[CH:23]=[CH:24][C:19]([CH2:18][OH:17])=[CH:20][CH:21]=3)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Product: O=c1ccc(-c2ccc(CO)cc2)cn1Cc1ccc(Cl)cc1
Yield: 52.1 %

Procedure:
According to Scheme 25 Step 2: The title compound was prepared from 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 3.30 mmol, 1.00 g, Example 2 Step 1) and 4-(hydroxymethyl)phenylboronic acid (1.5 eq, 5.00 mmol, 0.76 g) according to the procedure described for Example 1 Step 3. Reaction conditions: overnight at 80° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 70 g SiO2) using CH2Cl2/MeOH 98/2 as the eluent to afford 1-(4-chlorobenzyl)-5-(4-(hydroxymethyl)phenyl)pyridin-2(1H)-one (1.72 mmol, 0.62 g, 52%) as a brown oil LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=3.47 min; MS m/z (CI) [MH]+=326, 328.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.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>[NH:29]1[CH:28]=[C:27]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=[N:30]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 125 °C

Procedure:
To a mixture of 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 0.0049 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 0.0074 mol) in DMF (40 mL, 0.5 mol) was added potassium carbonate (2.0 g, 0.015 mol) in 15 mL of water. The mixture was purged with a steady stream of nitrogen for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.00036 mol) was added and the reaction was heated to 125° C. for 30 min. The mixture was allowed to cool then diluted with ethyl acetate. The diluted reaction mixture was washed with water, brine, dried over Na2SO4 and concentrated to give a solution in a small volume of DMF (about 2-3 mL). Water was added, causing the material to form a gum on the walls of the flask. Then water was decanted, and the solids were dissolved in ethyl acetate. The solution was dried over Na2SO4, and concentrated in vacuo to afford a yellow solid. The product was triturated with ethyl ether to yield 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as a white powder which was dried under vacuum (1 g, 60%). 1H NMR (300 MHz, CDCl3): δ 10.80 (br s, 1H), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 3.61 (dd, 2H), 0.98 (dd, 2H), 0.00 (s, 9H); MS (ES): 316 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Cl:14][C:15]1[C:16](F)=[CH:17][C:18]([F:28])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:14][C:15]1[C:16]([O:13][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([Cl:1])[CH:3]=2)=[CH:17][C:18]([F:28])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: Oc1ccc(OC(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
3-chloro-4-(trifluoromethoxy)phenol (22.6 g, 0.106 mol) and tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 26.4 g, 0.106 mol) were dissolved in dimethlysulfoxide (105 mL). Then potassium carbonate (29.4 g, 0.213 mol) was added portionwise to the mixture, which was stirred at room temperature for 18 hours. The reaction mixture was dropped into iced water (500 mL) and stirred vigorously for 4 hours. The resulting solid was collected by filtration then taken up in isopropanol (75 mL) and water (15 mL). The reaction was heated to 55° C., then cooled down to room temperature. The resulting solid was collected by filtration to yield the title compound as an off-white white solid (35.3 g, 75%).
Reaction SMILES: [N+:1]1([O-:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[O:21].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[OH-].[Na+]>O.ClCCl>[O-:13][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:27][CH:28]=2)=[O:21])=[CH:3][CH:2]=1
Reactant: O=Cc1cc[n+]([O-])c2ccccc12
Reactant: Nc1ccsc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1sccc1NCc1cc[n+]([O-])c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of quinoline-4-carboxaldehyde 1-oxide (0.12 g, 0.69 mmol), 3-amino-N-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide (0.21 g, 0.69 mmol), dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was heated at 50° C. for 2 hr, then cooled to room temperature, treated with triethylsilane (0.22 ml, 1.38 mmol) and stirred at 50° C. for another 2 h. After this time the mixture was diluted with water (40 ml), basified (pH 9) with 2M NaOH (aq) and extracted with ethyl acetate (3×20 ml). The extracts were washed with water (30 ml) and brine (30 ml), then dried (MgSO4) and concentrated in vacuo to give crude product. This material was chromatographed over silica gel eluting with 15% acetonitrile/CH2Cl2, and the isolated product further purified by crystallization from acetonitrile to give 3-{[(1-oxidoquinolin-4-yl)methyl]amino}-N-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide. MS (ES+): 460 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ 5.00 (s, 2H), 6.87 (d, J=5.6 Hz, 1H), 7.25-7.40 (m, 3H), 7.65 (d, J=5.3 Hz, 1H), 7.73-7.91 (m, 4H), 8.0 (t, J=6.4 Hz, 1H), 8.30 (d, J=7.1 Hz, 1H), 8.56 (d, J=6.3 Hz, 1H), 8.61 (d, J=8.3 Hz, 1H), 9.60 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CN([CH:28]=[O:29])C>>[C:1]1([C:7]2[N:8]=[C:9]([CH:28]=[O:29])[N:10]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1cc(-c2ccccc2)nc1C=O
Yield: 97.8 %

Procedure:
Reaction of 4-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (380 mg, 1.39 mmol), 2.5 M n-BuLi (720 uL, 1.80 mmol), and DMF (323 uL, 4.17 mmol) for 4 h at −40° C. gave the title compound (411 mg, 98%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.93 (t, 2H, J=9.0 Hz), 3.61 (t, 2H, J=9.0 Hz), 5.83 (s, 2H), 7.26-7.46 (m, 3H), 7.65 (s, 1H), 7.83 (d, 2H, J=9.0 Hz), 9.89 (s, 1H).
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.O.Cl>CO>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH:14]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
To a solution of sodium (60 g , 2.6 mol) in 1000 ml of methanol was added 5-fluoroindole (49 g, 0.36 mol) and 4-piperidone.H2O.HCl (170 g, 1.11 mol). The mixture was heated under reflux for 18 h, then concentrated , water was added and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated. The resulting solid was dissolved in methanol (about 200 ml) and then diluted with water (about 1000-1500 ml). The precipitate was collected , washed with water and petroleum ether and then dried in a vacuum oven at 60° C. Yield 74 g (95%) of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:18]([O:25][C:8]1[CH:9]=[C:2]([F:1])[C:3]([C:4]#[N:5])=[C:6]([F:11])[CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(F)cc(OCc2ccccc2)cc1F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a suspension of 2,4,6-trifluorobenzonitrile (314 mg, 2.00 mmol) and potassium carbonate (828 mg, 6.00 mmol) in dry N,N-dimethylformamide (3 mL) at 100° C. was added a solution of benzyl alcohol (216 mg, 2.00 mL) in dry N,N-dimethylformamide (1 mL) using a syringe pump over 4 h and the resulting mixture was stirred at 100° C. for 1 h. The reaction mixture was stirred at room temperature overnight and water and ethyl acetate were added and the phases separated. The organic phase was washed with 1.2 M hydrochloric acid (3×) and the combined organic phases were back-extractted with ethyl acetate (3×). The organic phases were dried (sodium sulfate), filtered, concentrated in vacuo and the residue was purified by flash chromatography (silica gel, hexanes-ethyl acetate 15:1) to give a white solid, mixture of regioisomers. The title product was obtained as a white solid (51 mg, 10%) by HPLC purification (reversed phase).
Reaction SMILES: CS(CCNCC1OC([C:14]2[CH:15]=[CH:16][C:17]3[N:23]=C[N:21]=[C:20](NC4C=CC(OCC5C=CC=C(F)C=5)=C(Cl)C=4)[C:18]=3[CH:19]=2)=CC=1)(=O)=O.NC1C=CC=CC=1C#N.[I:50]I.ICl>>[NH2:23][C:17]1[CH:16]=[CH:15][C:14]([I:50])=[CH:19][C:18]=1[C:20]#[N:21]
Reactant: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: II
Agent: ClI
Agent: N#Cc1ccccc1N
Product: N#Cc1cc(I)ccc1N

Procedure:
Accordingly, the basic raw material selected for the synthesis of Lapatinib of formula-(1) is commercially available 2-amino benzonitrile of formula-(6), which reacts with iodine or iodinemonochloride to get 2-amino-5-iodobenzonitrile of the formula-(7). The compound of the formula-(7) on reaction with a novel compound N1-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine (8) at elevated temperature gives the compound N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolinamine of formula-(3), The compound of the formula-(3) on reaction with 5-formyl-2-furyl boronic acid, in presence of triethylamine and Pd/C gives the compound 5-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-quinazolinyl)-furan-2-carbaldehyde of the formula-(4). The compound of the formula-(4), on reaction with 2-methanesulfonylethylamine hydrochloride gives the novel compound N[3-chloro-4[(3-fluorobenzyloxy]phenyl[-6-[5-({[2-methanesulphonyl)-ethyl]imino}-2-furyl]-4-quinazolinamine of the formula-(9). The novel imine compound of formula-(9) on reduction, using sodium borohydride gives the compound of the formula-(1), which is Lapatinib base. The reaction scheme of the present invention is as given the following Scheme-(C).