Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[N:19]=[C:20]3[N:24]([C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@@H:33]4[CH2:38][CH2:37][CH2:36][N:35]([S:39]([C:42]5[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=5)(=[O:41])=[O:40])[CH2:34]4)[N:27]=2)[CH:23]=[CH:22][S:21]3)[CH:13]=1)=[O:10])(C)(C)C.Cl>O1CCOCC1>[ClH:48].[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([S:39]([N:35]2[CH2:36][CH2:37][CH2:38][C@@H:33]([NH:32][C:28]3[N:27]=[C:26]([C:25]4[N:24]5[C:20]([S:21][CH:22]=[CH:23]5)=[N:19][C:18]=4[C:14]4[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][NH2:7])[CH:17]=[CH:16][CH:15]=4)[CH:31]=[CH:30][N:29]=3)[CH2:34]2)(=[O:41])=[O:40])=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 201.1 %

Procedure:
The tert-butyl{2-[(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)-pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)amino]-2-oxoethyl}carbamate (71 mg, 0.098 mmol) was dissolved in dioxane (3 ml) and treated with a 4N HCl solution in dioxane (1 ml). The mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was triturated in ether. Filtration afforded the title compound as a yellow solid (65 mg). M.p.=208-212° C. 400 MHz 1H NMR (DMSO-d6) δ: 10.69 (s, 1H), 8.18 (br. s, 3H), 8.13 (d, J=5.9 Hz, 1H), 7.88 (t, J=1.6 Hz, 1H), 7.79-7.75 (m, 2H), 7.71-7.66 (m, 3H), 7.48-7.43 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 6.45 (d, J=5.9 Hz, 1H), 5.15 (br. s, 3H), 4.04-3.95 (m, 1H), 3.79 (d, J=5.5 Hz, 2H), 3.70 (dd, J=11.3, 4.3 Hz, 1H), 3.48-3.41 (m, 1H), 2.57-2.48 (m, 1H), 2.42 (t, J=10.6 Hz, 1H), 1.95-1.82 (m, 2H), 1.67-1.54 (m, 1H), 1.48-1.37 (m, 1H). LCMS: 623 [M+H]. Calc. for C28H27N8O3S2Cl.2.52HCl: C, 47.03; H, 4.16; N, 15.67. Found C, 47.04; H, 3.97; N, 15.46.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[NH:19]1[CH:23]=[N:22][C-:21]=[N:20]1>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Reactant: [c-]1nc[nH]n1
Agent: [K]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC(n3cncn3)C2)cc1

Procedure:
To a solution of 2.55 g (10 mmole) of N-benzyl-3-[(methyl-sulphonyl)oxy]pyrrolidine in 100 ml of dimethylformamide was added 3.21 g of potassium-1,2,4-triazolide and the reaction mixture was heated at 85°-90° C. overnight. The same work up and purification procedure described in Example U afforded 1.32 g (15% methanol-ethyl acetate as solvent) of the title product. 1H NMR (CDCl3) δ: 8.3 (S, 1H), 7.93 (S, 1H), 7.6-7.1 (m, 5H), 5.2-4.6 (m, 1H), 3.67 (S, 2H), 3.23-2 (m, 6H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)(=[O:4])=[O:3].[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:8]([C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]=2[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[O:10])[CH2:30][CH2:31]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Product: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3NS(C)(=O)=O)CC2)c(C)c1
Yield: 55.5 %

Procedure:
Methyl 2-amino-4-nitrobenzoate (600 mg) and triethylamine (2.9 mL) were dissolved in tetrahydrofuran (11 mL), methanesulfonyl chloride (0.51 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. Methanol (18 mL) and 1N aqueous sodium hydroxide solution (9.1 mL) were added to the obtained residue, and the mixture was stirred at 50° C.-60° C. After completion of the reaction, to the reaction mixture was added aqueous sodium hydroxide solution, and the mixture was partitioned with ethyl acetate. The aqueous layer was neutralized with diluted hydrochloric acid, and the precipitated solid was collected by filtration to give 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg). Using the obtained 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg) and 1-(2,4-dimethylphenyl)piperazine (262 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (330 mg) was obtained. Then, to a solution of ethanol (5.4 mL) and water (1.8 mL) were added ammonium chloride (528 mg) and iron (379 mg), and the obtained N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (267 mg) was added while stirring at 60° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (268 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([CH3:12])[CH:4]=1.C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:20][C:9]1[N:8]2[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH3:12])=[CH:6][C:7]2=[N:11][CH:10]=1
Reactant: COc1cc(C)cc2nccn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)cc2ncc(Br)n12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of 5-methoxy-7-methylimidazo[1,2-a]pyridine (900 mg, 5.6 mmol) in carbon tetrachloride (100 mL), is added N-bromosuccimide (990 mg, 5.6 mmol). It is stirred at room temperature for 2 h. The reaction solution is then filtered through celite and the filtrate concentrated in vacuo. Ethyl acetate (150 mL) and water are added to the residue. The organic layer is separated and extracted with hydrochloric acid (1N, 3×100). The combined aqueous layer is neutralized with ammonium hydroxide at 0° C. and extracted with dichloromethane (3×200 mL). The combined organic layer is dried over sodium sulfate. The solvent is removed to give 3-bromo-5-methoxy-7-methylimidazo[1,2-a]pyridine (1.1 g, 78%) as a white solid, m.p. 105-106° C.
Reaction SMILES: C=O.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7]1.[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23].CO>C(O)C>[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23].[CH:15]1[C:13]2[C:14]3[N:6]4[CH2:5][CH2:4][NH:3][CH2:19][C:7]4=[CH:8][C:9]=3[CH2:10][CH2:11][C:12]=2[CH:18]=[CH:17][CH:16]=1
Reactant: NCCn1ccc2c1-c1ccccc1CC2
Agent: C=O
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: c1ccc2c(c1)CCc1cc3n(c1-2)CCNC3
Yield: 53 %

Procedure:
36% aqueous formaldehyde solution (1.4 ml) was added under argon to a solution of 3.7 g of 1-(2-aminoethyl)-4,5-dihydro-1H-benzo[g]indole in 70 ml of ethanol. The reaction solution was stirred under reflux for 2 hours, subsequently cooled and freed from solvent. The residue was chromatographed on 250 g of silica gel with methylene chloride/methanol (49:1) as the eluent. 1.3 g of a total of 2.8 g of product were dissolved in a 20-fold amount of hot ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. The precipitated solid was boiled in a 150-fold amount of methanol, filtered while hot and concentrated to a 60-fold amount of solvent. There were obtained 1.2 g (53%) of 5,6,8,9,10,11-hexahydrobenzo[g]pyrazino[1,2-a]indole fumarate (2:1); m.pt.: 183°-184° C. (dec.).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([NH:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>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>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([NH:12][C:13]([C:16]1[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=1)([CH3:15])[CH3:14])=[O:11])[CH2:2]2
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(NC(=O)NC1CN2CCC1CC2)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(NC(=O)NC1CN2CCC1CC2)c1cccc(-c2ccccc2)c1
Yield: 19.2 %

Procedure:
Using general procedure E, 1-(1-azabicyclo[2.2.2]oct-3-yl)-3-[2-(3-bromophenyl)propan-2-yl]urea (111 mg, 0.301 mmol), phenylboronic acid (78.8 mg, 0.606 mmol) and tetrakis(triphenylphosphine)palladium(0) gave the title compound as an off-white solid (21 mg, 11%). 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.52-7.40 (m, 8H), 4.89 (s, 1H), 4.28 (d, J=7.3 Hz, 1H), 3.75-3.59 (m, 1H), 3.15 (ddd, J=1.9, 9.3, 13.9 Hz, 1H), 2.46 (m, 4H), 2.05 (dd, J=3.5, 14.0 Hz, 1H), 1.68 (d, J=4.7 Hz, 6H), 1.66-0.76 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 157.4, 146.9, 142.5, 141.1, 129.7, 129.1, 127.8, 127.4, 126.7, 124.8, 124.7, 57.1, 55.1, 30.7, 30.1, 26.1, 26.0, 20.2 ppm. Purity: 100% UPLCMS (210 nm); retention time 0.78 min; (M+1) 364.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](C(N)=O)[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.C[O:23][CH:24]([O:28][CH3:29])N(C)C>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:24]([O:28][CH3:29])=[O:23])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: COC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a suspension of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide prepared as set forth in Example A-223 (2.9 g, 0.01 mol) in 50 mL of methanol was added N,N-dimethylformamide dimethyl acetal (3.67 g, 0.03 mol) dropwise. The reaction mixture was stirred at room temperature overnight and heated at reflux for 4hours. After cooling, the precipitate was collected by filtration and air-dried to give 2.0 g of methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate as a white solid (69% yield), mp: 239-241° C. Anal. Calc'd for C16H12FN3O2: C, 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:20])([CH3:19])[C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1csc(-c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C(=O)O)c1csc(-c2ccc(F)cc2)n1
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a stirred solution of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate (4.56 g, 15.5 mmol) in 1:1:1 THF/ethanol/water (45 mL) was added lithium hydroxide monohydrate (2.93 g, 69.8 mmol). The reaction was stirred overnight, concentrated and redissolved in water (175 mL). The solution was washed with ether (1×100 mL), acidified by the addition of 1.0 N HCl (80 mL) and extracted with ethyl acetate (2×70 mL). The combined extracts were dried (Na2SO4) and concentrated to afford 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid as a white solid (4.04 g, 98%). This material was used in the next step without purification.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][N:6]1[C:10]([C:11](=[O:28])[NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:21]=3)[CH:18]=2)=[C:9]([C:29](O)=[O:30])[CH:8]=[N:7]1>>[N:22]1([C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:11]([C:10]4[N:6]([CH3:5])[N:7]=[CH:8][C:9]=4[C:29]([CH:4]4[NH:1][CH2:2][CH2:3]4)=[O:30])=[O:28])=[CH:18][N:17]3[N:19]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Reactant: C1CNC1
Product: Cn1ncc(C(=O)C2CCN2)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1

Procedure:
Using azetidine and 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Light yellow solid (99 mg, 53%). MS: m/z=411 (M+H+). Ames test negative.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=2.[Br:22]Br.C(=O)([O-])O.[Na+]>O>[Br:22][C:12]1[C:11]([O:20][CH3:21])=[CH:10][CH:9]=[C:8]2[C:13]=1[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:6]([CH3:5])[NH:7]2
Reactant: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1c(C)[nH]c2ccc(OC)c(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an acetic acid (12 mL) solution of methyl [2-methyl-5-(methyloxy)-1H-indol-3-yl]acetate (300 mg), bromine (206 mg) was added and the mixture was stirred at room temperature for one hour. To the reaction mixture, water and an aqueous saturated sodium hydrogen carbonate solution were added, followed by extraction with ethyl acetate. The organic layer was washed in turn with an aqueous saturated sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=65:35→60:40) to obtain the titled compound having the following physical properties (134 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.[OH-].[Na+]>C(Cl)Cl>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:15][CH:16]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc(N4CCOCC4)cc3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1cc(N2CCOCC2)ccc1-c1ccc(C2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
5-(4-Morpholin-4-ylphenyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.37 g, 0.874 mmol) was dissolved in DCM (12 mL), TFA (4 mL) was added and the reaction mixture was stirred at RT for 1 hour, until all starting material had disappeared. Water and 1 N NaOH was added until pH=12. After extraction with DCM (4×40 mL) the DCM phase was dried with Na2CO3, filtered and evaporated to give 280 mg (100%) white crystals.
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CCOCC>[CH2:1]([O:5][S:14]([CH3:13])(=[O:16])=[O:15])[C:2]#[C:3][CH3:4]
Reactant: CC#CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC#CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
2-Butyne-1-ol (1.4 g, 20 mmol) is dissolved in ether (50 mL) and cooled to 0° C. Triethylamine (3.3 mL, 24 mmol) is added to the solution. Methanesulfonyl chloride (1.6 mL, 22 mmol) is dissolved in ether (5 mL) and added dropwise to the reaction solution. The mixture is stirred for 30 minutes at 0° C., then filtered and concentrated to give crude methanesulfonic acid but-2-ynyl ester 20 (2.96 g, 20 mmol, quant.) as a colorless liquid: 1H-NMR (400 MHz, CDCl3) δ=4.79 (q, J=2.4 Hz, 2H), 3.08 (s, 3H), 1.87 (t, J=2.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:11](=[CH:10][CH:9]=[N:8][CH:7]=2)[NH:6]1)=[O:4]
Reactant: COC(=O)c1ccc2cccnc2n1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCc2cnccc2N1

Procedure:
1,6]naphthyridine-2-carboxylic acid methyl ester (1 equiv.) and methanol (anhydrous, 5 mL) were combined in a reaction vessel under nitrogen atmosphere. Palladium, 5% wt. on calcium carbonate (1 equiv.) was added and hydrogen gas was bubbled through the solution via balloon for 12 h. The reaction was passed through a short plug of silica to remove the catalyst and the silica plug was washed with 20% methanol in DCM. The solvent was removed in vacuo to yield the title compound as a brown solid weighing 12 mg (59%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[O:31][C:32]=3[CH3:33])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2nn(Cc3ccccc3)cc2CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of ethyl 1-benzyl-3-({3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate (1.50 g) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (0.22 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (1.86 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give (1-benzyl-3-({3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazol-4-yl)methanol as a colorless oil (1.25 g, yield 89%).
Reaction SMILES: [CH2:1]([N:4]([CH3:9])[CH2:5][C@@H:6]([OH:8])[CH3:7])[CH:2]=[CH2:3].F[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2>>[CH2:1]([N:4]([CH3:9])[CH2:5][C@H:6]([CH3:7])[O:8][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2)[CH:2]=[CH2:3]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Reactant: C=CCN(C)C[C@H](C)O
Product: C=CCN(C)C[C@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Yield: 92 %

Procedure:
The procedure described in Example 103, preparation of starting materials, was repeated using (2S)-1-[allyl(methyl)amino]propan-2-ol (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) and 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials) to give 5-{(1S)-2-[allyl(methyl)amino]-1-methylethoxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine in 92% yield as a gum; Mass spectrum: MH+ 470.
Reaction SMILES: C(OC([C:6](=[C:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O)C.C(=O)=O.[OH-].[Na+]>Cl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=C1CCCN1C)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Product: CN1CCCC1Cc1ccc(Cl)cc1
Yield: 92 %

Procedure:
Boil 40 g of 2-(α-ethoxycarbonyl-4-chlorobenzylidene)-1-methylpyrrolidine and 150 ml of conc. hydrochloric acid under reflux until the cessation of evolution of carbon dioxide. Cool the thus-obtained reaction mixture and then render it alkaline with 10% strength solution of sodium hydroxide before extracting the resulting product with 5×70 ml of diethyl ether. After drying over sodium sulfate, concentrate the ether extract to a solid residue. Hydrogenate the solid residue in 550 ml of ethanol with Pt/hydrogen to obtain 27.6 g of the title compound having a boiling point of 75° at 0.005 mm of Hg.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([Br:14])[N:13]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.O.[Cu]I.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>[Br:14][C:12]1[N:13]=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:9]([NH2:15])=[N:10][CH:11]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
(Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine (5 g, 19.77 mmol), triethylamine (10.00 g, 13.77 mL, 98.85 mmol), Copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) in DMF (25.00 mL) and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organics washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15% EtOAc/Petroleum ether to give the product as a yellow solid (3.99 g, 75% Yield). 1H NMR (400.0 MHz, DMSO) d 0.30 (9H, s), 8.06 (1H, s); MS (ES+) 271.82
Reaction SMILES: [CH3:1][NH2:2].CO.[CH2:5]([O:7][CH:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:24])[C:19](OCC)=[O:20])[CH3:9])[CH3:6].C1COCC1>O>[CH2:5]([O:7][CH:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:24])[C:19]([NH:2][CH3:1])=[O:20])[CH3:9])[CH3:6]
Reactant: CCOC(=O)C(=O)c1ccccc1COC(C)OCC
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(C)OCc1ccccc1C(=O)C(=O)NC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A 40% methylamine-methanol solution (1.63 g, 0.021 mol) was added to a mixed solution of ethyl 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-oxoacetate (1.96 g, 0.007 mol) and THF (7 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane (80 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (1.35 g, Yield: 72.7%) as a colorless oil. 1H-NMR (CDCl3) δ ppm: 1.17(3H,t,J=7.3), 1.29(3H,d,J=4.9), 2.96(3H,d,J=5.5), 3.41-3.63(2H,m), 4.70-4.92(3H,m), 7.04(1H,brs), 7.33-7.84(4H,m).