Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([N:12]([CH3:18])[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])(=[O:11])=[O:10].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21]>CC(C)=O>[CH3:8][S:9]([N:12]([CH3:18])[N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21])(=[O:10])=[O:11]
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CN(NS(C)(=O)=O)S(C)(=O)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(OC(=O)N(N(C)S(C)(=O)=O)S(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
1,2-Bis(methylsulfonyl)-2-[(4-methoxyphenoxy)carbonyl]-1-methylhydrazine (compound 9) was synthesized as follows: Triethylamine (0.269 g, 0.0029 mol) was added to a stirred solution of 1,2-bis(methylsulfonyl)-1-methylhydrazine (0.50 g, 0.0025 mol) and 4-methoxyphenyl chloroformate (0.63 g, 0.0033 mol) in acetone (30 ml) and the mixture stirred for 1 hr. The reaction mixture was filtered and the filtrate evaporated to dryness in vacuo. The residue was triturated with petroleum ether (5 ml) and the petroleum ether layer decanted. Column chromatography of the residue on silica gel (70-270 mesh, 60 Angstroms, CHCl3), followed by crystallization from ethanol gave 0.14 g (16.1%) of the desired compound. Mp was approximately 101-102° C. 1H NMR (acetone-d6) : δ 7.3 and 7.0 (4H, 2d, aromatic H), 3.9 (3H, s, OCH3), 3.6, 3.4 and 3.2 (9H, 3s, 2 CH3SO2 and NCH3).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[CH3:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]([NH:24][CH:25]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[CH:21]=[CH:22][CH:23]=1)=[O:17]>C(OCC)(=O)C.C(#N)C>[Cl-:1].[CH3:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]([NH:24][CH:25]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N+:31]([CH2:2][C:3]4[N:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[O:5][N:4]=4)([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[CH:21]=[CH:22][CH:23]=1)=[O:17]
Reactant: CNC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Reactant: ClCc1noc(-c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CNC(=O)c1cccc(NC(C(=O)O[C@H]2C[N+]3(Cc4noc(-c5ccccc5)n4)CCC2CC3)c2ccccc2)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.5 %

Procedure:
3-(Chloromethyl)-5-phenyl-1,2,4-oxadiazole (I45) (53.9 mg, 0.28 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(3-(methylcarbamoyl)-phenylamino)-2-phenylacetate (I10) (99 mg, 0.252 mmol) in a mixture of ethyl acetate (3.3 ml) and acetonitrile (1.7 ml). The reaction was stirred at room temperature for 2 days. Then the solution was evaporated and the residue was triturated with EtOAc (10 ml). The suspension was filtered on a buckner funnel, and the solid was recovered and further purified by flash chromatography (DCM/MeOH=85/15) to obtain (R)-3-(2-(3-(methylcarbamoyl)phenylamino)-2-phenylacetoxy)-1-((5-phenyl-1,2,4-oxadiazol-3-yl)methyl)-1-azoniabicyclo[2.2.2]octane chloride (23 mg, 15% yield, mixture of diastereomers).
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=O)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.B.CSC.CO>O1CCCC1>[N:1]1[C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2cccnc2Oc2ccccc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: c1ccc2c(c1)CNc1cccnc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
A mixture of 2.8 g of pyrido[2,3-b][1,4]benzoxazepin-6(5H)-one, 10 ml of tetrahydrofuran and 3 ml of 10M borane-dimethylsulfide in tetrahydrofuran is stirred at room temperature overnight and then refluxed for 3 hours. To the mixture is added dropwise under argon, 5 ml of methanol. The solvent is removed under vacuum and methanol added. The solvent is removed under vacuum and 12 ml of 2N NaOH added to the residue. The mixture is refluxed for 2 hours and extracted with ethyl acetate. The extract is washed with 2N citric acid, H2O, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum. The residue is chromatographed on a column (2"×18") of silica gel (32° g) with hexane-ethyl acetate (1:1) as solvent to give 0.78 g of crystals, m.p. 172°-174° C.
Reaction SMILES: [C@@H:1]1([C:10](Cl)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7](Cl)=[O:8].[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[NH2:18]>C1C=CC=CC=1>[F:13][C:14]([F:25])([F:26])[C:15]1[CH:16]=[C:17]([NH:18][C:10]([C@@H:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]2[C:7]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:15]([C:14]([F:13])([F:25])[F:26])[CH:16]=2)=[O:8])=[O:11])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C(Cl)[C@@H]1CCCC[C@H]1C(=O)Cl
Solvent: c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)[C@@H]1CCCC[C@H]1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
Reflux a mixture of 16.73 g (0.08 moles) of trans-1,2-cyclohexane dicarboxylic acid chloride and 32.96 g (0.16 moles) of 3-trifluoromethyl-4-nitroaniline in 250 ml of benzene for 1.5 hours. Isolate the solid product of this example by filtering, washing well with hot benzene followed by ether and obtain analytically pure material by recrystallization from benzenemethanol, mp 249.5°-251° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([CH2:28][CH3:29])=[N:19][N:20]3[C:25]([NH2:26])=[CH:24][C:23](Cl)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([CH2:28][CH3:29])=[N:19][N:20]3[C:25]([NH2:26])=[CH:24][C:23]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCNCC1
Reactant: CCc1nn2c(N)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nn2c(N)cc(N3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 49.9 %

Procedure:
0.33 ml (3 mmol) of 1-methyl-piperazine was added to a solution of 0.4 g (1.2 mmol) of 3-benzenesulphonyl-5-chloro-2-ethyl-pyrazolo[1,5-a]pyrimidin-7-ylamine in 5 ml of DMF and stirred at 90° for 1 hr. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was extracted three times with 50 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH 9:1) and crystallization from EtOH yielded 0.24 g (50%) of 3-benzenesulphonyl-2-ethyl-5-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidin-7-yl-amine as colorless crystals, m.p.>250°.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:13][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([O:6][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)CCC(O)c1ccccc1
Product: CN(C)CCC(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 88.5 %

Procedure:
Following the procedure of Example 3, 17.9 g of 3-dimethylamino-1-phenyl-1-propanol and 14.1 g of 1-fluoro-4-nitrobenzene were reacted to provide 26.54 g of the subtitle intermediate as a red oil. Preparation of the oxalate salt of a small portion of the oil provided yellow crystals with a melting point of 155°-157° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=[O:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[CH3:22][S-:23].[Na+]>O1CCOCC1.O>[CH3:19][C@H:14]1[O:15][C@@H:16]([CH3:18])[CH2:17][N:12]([C:9]2[C:8]([CH:20]=[O:21])=[CH:7][C:6]3[C:2]([S:23][CH3:22])=[N:3][O:4][C:5]=3[C:10]=2[F:11])[CH2:13]1
Reactant: C[S-]
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice cold solution of 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde (Intermediate 534, 0.3 g, 0.916 mmol) in dioxane was added sodium thiomethoxide (21% aq solution, 0.134 mL, 1.923 mmol) and stirred at room temperature for 12 hours. Reaction mixture was diluted with water and extracted with EtOAc (50 mL). Organic phase washed with brine (2×10 mL), dried over anhydrous sodium sulfate and, filtered, concentrated to give tilt product as white solid. Yield: 280 mg (90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl[C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:25]=[CH:26][C:27]([C:40]3[CH:45]=[N:44][CH:43]=[CH:42][N:41]=3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: Clc1cnccn1
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3cnccn3)cc2)n1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrazin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one is prepared from 5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one and 2-chloro-pyrazine by using the method described in example 338 except that the reaction mixture is stirred at 100° C. for 14 hours: 1H NMR (CDCl3) δ (ppm) 9.02(d, 1H), 8.67(t, 1H), 8.55(d, 1H), 8.35(s, 1H), 8.15 (d, 2H), 7.95(d, 2H), 7.51(m, 4H), 7.37 (t, 1H), 7.33(d, 2H), 7.14(d, 2H). HPLC-MS calculated C27H17ClN6O (M+1+): 477.1. Found: 477.1.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([C:19]([NH:21][NH2:22])=[O:20])=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.FC(F)(F)[C:25](O)=[O:26].Cl[CH2:31]Cl>>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([C:19]3[O:20][C:25](=[O:26])[N:22]([CH3:31])[N:21]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: ClCCl
Reactant: NNC(=O)c1cc(C(F)(F)F)n(-c2ccc([N+](=O)[O-])nc2)n1
Reactant: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cc(C(F)(F)F)n(-c3ccc(N)nc3)n2)oc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Step-5: 1-(6-Nitropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbohydrazide: To a (0° C.) cooled solution of step-4 intermediate (2.0 g, 4.80 mmol) in dichloromethane (25 mL) was added drop-wise trifluoroacetic acid (3.70 mL, 48.0 mmol). After stirring the reaction mixture at room temperature for 18 h, the solvent was evaporated under reduced pressure. The crude product was triturated with diethyl ether to obtain 1.32 g (87%) of the title compound as semi solid. The residue was used for next step without further purification. ESI-MS (m/z) 317 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]([OH:15])=O)[CH2:9][CH2:10][CH3:11])=[O:7])([CH3:4])(C)C.[C:16]12([NH2:26])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.[CH:27](N(CC)C(C)C)(C)[CH3:28]>C(Cl)Cl>[C:16]12([NH:26][C:13](=[O:15])[CH2:12][N:8]([C:6]([O:5][CH2:1][CH2:4][CH2:27][CH3:28])=[O:7])[CH2:9][CH2:10][CH3:11])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCCOC(=O)N(CCC)CC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
Next, methylene chloride (208 ml) was added to a mixture of 2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid (4.52 g, 20.8 mmol) and 1-adamantaneamine (3.46 g, 22.9 mmol), and the whole was stirred at room temperature. N,N-Diisopropylethylamine (7.25 ml, 41.6 mmol) and then O-(7-azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate (8.71 g, 22.9 mmol) were added thereto, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 7.88 g (quantitatively) of 2-[N′-(butoxycarbonyl)-N′-propylamino]acetic acid N-(1-adamantyl)amide as a colorless oily matter. The obtained oily matter solidified at room temperature.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20](O)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(Cl)(=O)OCC.[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:17][CH2:16][C:15]([CH2:20][OH:21])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: O=C(NC12CCC(CO)(CC1)CC2)OCc1ccccc1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
4-Benzyloxycarbonylaminobicyclo[2,2,2]octane-1-carboxylic acid (500 mg) was dissolved in tetrahydrofuran (8 mL). While the solution was chilled in a salt/ice bath, N-methylmorpholine (0.18 mL) was added. This was followed by dropwise addition of ethyl chlorocarbonate (0.16 mL) and stirring for 10 minutes. To the reaction mixture, sodium borohydride (187 mg) and then methanol (15 mL) were added and the mixture was stirred below 0° C. for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure. To the resulting residue, water was added and the solution was extracted with ethyl acetate. The ethyl acetate layer was then washed sequentially with 1 mol/L hydrochloric acid and water, was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluant: hexane: ethyl acetate=1:1) to obtain 4-benzyloxycarbonylamino-1-hydroxymethylbicyclo[2,2,2]octane (453 mg).
Reaction SMILES: [Br:1][C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][C:9]([C:15]([O:17]C)=[O:16])=[CH:8][C:7]=3[NH:6][C:5](=[O:19])[C:4]=2[CH:3]=1.CO.C1COCC1.O.[Li+].[OH-].Cl>O>[Br:1][C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][C:9]([C:15]([OH:17])=[O:16])=[CH:8][C:7]=3[NH:6][C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Methyl 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 17 mg, 0.050 mmol) was suspended in a 1:1:1 mixture of MeOH/THF/water (0.6 ml). LiOH (39 mg) was added and the mixture stirred at room temperature for one hour. Water and 6N HCl was added and the resulting precipitate was filtered. The material was purified by preparative HPLC. Genevac evaporation provided 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylic acid as a solid (2.1 mg, 13% yield). LCMS (ES): >95% pure, m/z 324 [M]+, 326[M+2]+; 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.75 (dd, J=1.6, J=8.0, 1H), 7.90 (d, J=8.4, 1H), 8.03 (d, J=1.6, 1H), 12.06 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:40][O:41][C:42](=[O:47])[CH2:43][C:44](Cl)=[O:45]>CCOC(C)=O>[CH3:40][O:41][C:42](=[O:47])[CH2:43][C:44]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1)=[O:45]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: COC(=O)CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (22 mg, 0.04 mmol, Example 25: step c) was dissolved into THF (1 mL) and to this was added chlorocarbonyl-acetic acid methyl ester (9 μL, 0.085 mmol). The reaction was heated to 50° C. for 5 hours and then allowed to stir at RT for 48 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by purification by preparative TLC (SiO2) (30% EtOAc in hexanes) that yielded the title compound. ESI-MS (m/z): Calcd. for C28H31N3O7S3: 618.1 (M+1) found: 617.9.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([O:12][C:13](=[O:15])[CH3:14])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:21][C:22](=[CH2:24])[CH3:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:22]([O:10][C:9](=[O:11])[C@H:8]([O:12][C:13](=[O:15])[CH3:14])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:24])([CH3:23])[CH3:21]
Reactant: C=C(C)C
Reactant: CC(=O)O[C@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Cool to -30° to -20° C., 3-phenyl-2(R)-acetoxypropionic acid (10.5 g) in CH2Cl2 (200 mL), add conc. H2SO4 (0.5 mL) and isobutylene (120 mL), seal the vessel, and stir at room temperature for 2 days. Vent the vessel, pour the reaction mixture into NaHCO3 solution, and extract with CH2Cl2. Dry the CH2Cl2 extract (MgSO4), then concentrate in vacuo to give 3-phenyl-2(R)-acetoxypropionic acid t-butyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>CN(C)C=O>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:24])[O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][CH2:4][CH2:3][N:2]2[CH3:1])=[CH:7][CH:8]=1
Reactant: CN1CCCc2ccc(O)cc21
Reactant: O=C=Nc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCc2ccc(OC(=O)Nc3ccccc3F)cc21
Reaction time: 0.5 h

Procedure:
A solution of 1-methyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) in dry dimethylformamide (DMF, 5 mL) was added to the stirred solution of sodium hydride in dry DMF at −10° C. during 5 minutes under nitrogen environment. The reaction mixture was stirred for 30 minutes. Then, 2-fluorophenyl isocyanate (352 mg/ml, 3.14 mM) was added to the stirring reaction mixture. The mixture was stirred further for 3 hours during which the temperature was allowed to reach the room temperature (37° C.). The reaction mixture was quenched with water, diluted with water, extracted with ethyl acetate and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford the pure compound 8l as oil. Yield: 580 mg, 63.03%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[NH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39].C[OH:43]>ClCCl.[Pd]>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:38]([O-:40])(=[O:43])=[O:39])=[CH:12][CH:11]=1.[CH3:41][S:38]([CH2:37][CH2:36][NH:35][CH2:33][C:31]1[O:32][C:28]([C:25]2[CH:24]=[CH:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([NH:17][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=5)=[C:2]([Cl:1])[CH:3]=4)[C:27]=3[CH:26]=2)=[CH:29][CH:30]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)CCN
Reactant: CO
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: [Pd]
Solvent: ClCCl
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
The suspension of 5-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-quinazolin-6-yl]-2-furaldehyde (10 g, 21.1 mmoL) in dichloromethane (100 mL) was charged with a solution of 2-aminoethylmethylsulfone (5.8 g, 46.4 mmoL) in methanol (50 mL) slowly under constant stirring at room temperature. The reaction mixture was stirred for 2-4 hours until reaction completion and then was charged with 5% Pd—C (0.5 g) and stirred under hydrogen atmosphere at 25 psi pressure for 16-24 hours until reaction completion. The obtained mixture was filtered, washed with a 3:1 mixture of methanol (40 mL) and dichloromethane (20 mL). The filtrate was distilled to low volume, and the obtained solution was slowly charged with solution of p-toluenesulfonic acid monohydrate (4.4 g, 23.2 mmoL) in methanol (10 mL). The yellow solid which precipitated out was filtered and washed with a 1:1 mixture of methanol (20 mL) and dichloromethane (20 mL). The solid obtained was dried under vacuum at 40-45° C. to give the monotosylate salt of Lapatinib (11.4 g, Yield=72%, HPLC purity>99%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.Cl.[C:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:10]([O:14][C:15](=[O:19])[C@@H:16]([NH:17][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:8])[CH3:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(O)c1ncc[nH]1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ncc[nH]1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (0.17 g) in N,N-dimethylformamide (DMF) (3 mL) was added alanine tert-butyl ester hydrochloride (0.22 g), diisopropylethyl amine (0.27 mL) and HOBT (0.41 g) before cooling to 0° C. and the reaction mixture was then treated with EDC HCl (0.32 g). The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 18 hrs before being diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and concentrated at reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford the sub-title compound as a colourless oil (0.263 g, 73%): 1H NMR 400 MHz CDCl3 1.50 (9H, s), 1.51 (3H, d, J 7.2), 3.70 (1H, m), 7.28 (2H, s), 7.78 (1H, d, J 7.6), 11.49 (1H, br s).
Reaction SMILES: [N+](=[C:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])=[N-].[CH3:16][OH:17]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH:3]([O:17][CH3:16])[C:4]([O:6][CH3:7])=[O:5])=[CH:10][CH:11]=1
Reactant: CO
Reactant: COC(=O)C(Cc1ccc(O)cc1)=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(O)cc1)OC
Reaction time: 15 h

Procedure:
A solution of methyl 2-diazo-3-(4hydroxyphenyl)propanoate (cf Tetrahedron Lett., 1971,4495) (8.58 g) in methanol (120 mL) was added over 10 minutes to a mixture of rhodium (II) acetate dimer (0.18 g) in methanol (50 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was heated at reflux for 5 hrs, allowed to stand at room temperature for 15 hrs, then concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL), washed with water (3×300 mL) and brine (500 mL), dried (MgSO4) and evaporated. The resulting gum was chromatographed on silica gel with a gradient of 4% ethyl acetate to 6% ethyl acetate in dichloromethane as eluent to afford the title compound, mp 61-3° C.