Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][S:11]([C:14]1[C:15]([O:40][CH2:41][CH2:42][CH3:43])=[C:16]([O:38][CH3:39])[CH:17]=[C:18]([C:20](=[O:37])[CH2:21][CH2:22][C:23]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)=[O:24])[CH:19]=1)(=[O:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(OCC)(=O)C>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][S:11]([C:14]1[C:15]([O:40][CH2:41][CH2:42][CH3:43])=[C:16]([O:38][CH3:39])[CH:17]=[C:18]([CH:20]([OH:37])[CH2:21][CH2:22][C:23](=[O:24])[C:25]2[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=2)[CH:19]=1)(=[O:13])=[O:12])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCOc1c(OC)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCOc1c(OC)cc(C(O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(5-(2-t-butyldimethylsilyloxyethylsulfonyl)-4-n-propoxy-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)butan-1,4-dione (1.076 g, 1.70 mmole) at 0° C. in dry THF (40 mL) under nitrogen was treated with lithium tri-t-butoxyaluminum hydride (500 mg, 2 mmole), and the mixture was stirred at 0° C. for 1 hour. The reaction was allowed to warm to room temperature and stirred for 3 hours. The mixture was poured into ethyl acetate (500 mL), and the ethyl acetate solution was washed with 1 N HCl (2×100 mL), water and brine, dried over anhydrous MgSO4, and evaporated to dryness. The crude product was purified by flash column chromatography on SiO2 and eluted with 40% hexane ethyl acetate (3:2 v/v) to provide the pure title product as a thick syrup.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14].C(N(CC)CC)C.C1COCC1>C(OCC)C>[C:17]([O:16][C:12]([NH:13][NH:14][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc(C#N)c(NNC(=O)OC(C)(C)C)n1
Reaction time: 22 h
Yield: 83 %

Procedure:
4-Chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (prepared as described in US2003158218, 0.509 g, 2.74 mmol), tert-butyl carbazate (tert-butoxycarbonyl hydrazine, 0.403 g, 3.05 mmol) and triethylamine (0.57 mL, 4.1 mmol) were added to 25 mL THF. The reaction mixture was stirred 22 hours, and then 25 mL diethyl ether was added and the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and the resulting oil was chromatographed through silica (0%-33% EtOAc in hexanes) to give 0.64 g of N′-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-hydrazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>C(O)C>[CH3:13][O:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1onc(O)c1C
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)c1onc(OC)c1C
Temperature: 40 °C

Procedure:
A mixture of ethyl 3-hydroxy-4-methylisoxazole-5-carboxylate (2.0 g, 11.7 mmol) and K2CO3 (4.0 g, 29 mmol) in ethanol (50 mL) was heated at 40° C. for a total of 26 h. Methyl iodide (0.8 mL, 13 mmol) was added after 1 h and an additional 3 times during the next 25 h. The solution was filtered and reduced in vacuo (according to 1H NMR, a 1:1 mixture of the title compound and ethyl 3-methoxy-4-methylisoxazole-5-carboxylate was obtained). Flash chromatography (silica gel, eluent: dichloromethane/diethyl ether=9:1 then 1:1) gave ethyl 3-Methoxy-4-methylisoxazole-5-carboxylate as a yellow oil (0.40, 18%) and title compound (0.45 g, 21%). A small sample of the latter was recrystallized (EtOAc/heptane) to give colorless crystals: mp 64-65° C. Crude title compound was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[N:11][NH:12][CH:13]=1.[C:22](Cl)(=[O:24])[CH3:23].O>CN(C)C1C=CN=CC=1.C1COCC1>[C:22]([N:12]1[CH:13]=[C:9]([Cl:8])[C:10]([C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[N:11]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Clc1cc(Cl)cc(-c2n[nH]cc2Cl)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)n1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 2 h
Yield: 96.7 %

Procedure:
0.35 g (0.003 mol) of 4-dimethylaminopyridine and 1.55 ml (0.011 mol) of triethylamine are added to 2.55 g (0.01 mol) of 4-chloro-3-(3,5-dichlorophenyl)-pyrazole dissolved in 30 ml of THF. A solution of 0.85 g (0.011 mol) of acetyl chloride in 10 ml of THF is run, dropwise and at 0° C., onto this solution. Stirring is continued for 2 h at room temperature. The reaction mixture is poured into 100 ml of water and extracted with ethyl acetate. After drying the organic phase and concentration under vacuum, the residue is triturated with 50 ml of heptane, filtered and dried. We obtain 2.80 g of 1-acetyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 125° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:12][C:11]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]3[C:10]=2[N:9]=[CH:8][N:7]=[C:6]3[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1NC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Yield: 9.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 7-methyl-N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-37, 140 mg, 0.44 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 163 mg, 0.57 mmol), oxalyl chloride (108 mg, 0.86 mmol), DMF (1 drop) and DIPEA (170 mg, 1.32 mmol) in CH2Cl2 (5 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.71 (s, 1H), 10.03 (s, 1H), 8.72 (s, 1H), 8.46 (d, J=8.4 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J=9.3 Hz, 1H), 8.19 (t, 1H), 7.66-7.63 (m, 2H), 7.46 (d, J=6.9 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.31 (t, J=8.1 Hz, 1H), 4.33 (d, J=5.4 Hz, 2H), 2.50 (s, 3H), 1.15 (s, 9H); MS (m/z): 588.23 (M)+.
Reaction SMILES: CO[C:3](=[O:5])[O-:4].[CH3:6][N+:7]1([CH3:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.C1(=O)[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>O>[C:3]([O-:4])(=[O:5])/[CH:15]=[CH:16]\[C:17]([O-:19])=[O:18].[CH3:6][N+:7]1([CH3:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:6][N+:7]1([CH3:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=C1C=CC(=O)O1
Reactant: COC(=O)[O-]
Agent: C[N+]1(C)CCOCC1
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]
Yield: 132.9 %

Procedure:
By following the same procedure as Example 20 (2nd step) except that 19.1 g of N,N-dimethylmorpholinium methyl carbonate, 19.1 g of water, and 9.8 g of maleic anhydride were used, 23.0 g (yield of 99.9%) of N,N-dimethylmorpholinium maleate was obtained. The content of monomethyl maleate was less than 0.1% and the contents of impurity ions were all less than 1 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C:33]1[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=1[C:35]([O:37]C)=[O:36])[S:9]([C:12]1[CH:17]=[C:16]([C:18](=[O:30])[NH:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH:21]2[CH3:29])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C(#N)C.O>[C:1]([O:5][C:6]([N:8]([CH2:32][C:33]1[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=1[C:35]([OH:37])=[O:36])[S:9]([C:12]1[CH:17]=[C:16]([C:18](=[O:30])[NH:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH:21]2[CH3:29])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:11])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccccc1CN(C(=O)OC(C)(C)C)S(=O)(=O)c1cc(C(=O)NN2c3ccccc3CC2C)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(=O)(=O)N(Cc2ccccc2C(=O)O)C(=O)OC(C)(C)C)c1

Procedure:
Dissolve the compound obtained in Step A (1.26×10−3 mol) in a mixture of acetonitrile (45 ml) and water (9 ml). Add lithium hydroxide (1.26×10−2 mol) and heat at 50° C. with stirring. After heating for 5 hours and 30 minutes, the dark-brown reaction mixture is poured into water (100 ml). Extract 3 times with ethyl acetate (50 ml). The organic phase is then washed with water and then with brine, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=4)[CH2:10][CH2:11]3)=[O:16])=[CH:18][CH:19]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(C)=O)C4=O)cc3)CC2)c(C)c1
Yield: 91.7 %

Procedure:
Using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (1.09 g) described in Preparation Example 133 and 1-acetylimidazolidin-2-one (384 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.00 g) was obtained.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH:38]1([CH2:37][NH:36][S:33]([C:29]2[CH:28]=[C:27]([NH:26][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH2:39][CH2:40]1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCC2CC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCC2CC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-cyclopropylmethyl-benzenesulfonamide (example B.2) according to general procedure II. Yellow solid. MS (ISP) 564.2 [(M−H)−]; mp 238° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[C:4]([Cl:10])[C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O.Cl>>[Cl:1][C:2]1[C:7]([N+:12]([O-:14])=[O:13])=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[Cl:11]
Reactant: O=[N+]([O-])O
Reactant: Clc1cc(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 125 °C

Procedure:
Into a three-neck 300 ml flask equipped with a mechanical agitator, thermometer and condenser was charged 50 g of 99.7% pure powdered pentachlorobenzene which was heated to 105°-110° C. by means of an oil bath. The flask was then charged with 113 g of mixed nitric acid which contained 16.5% by weight nitric acid and 83.5% by weight sulfuric acid. This mixed nitric acid was gradually added over a period of three hours while the reaction mixture was stirred. Following this addition, the reaction mixture was heated to 125° C. for one hour, followed by further heating at 140° C. for one hour. Then, 7 g of HCl was gradually added over a time period of 15 minutes. After said HCl addition, the reaction mixture was heated again to raise the reaction temperature to 145° C. and to form a liquid melt of pentachloronitrobenzene. The reaction mixture was maintained at this temperature for 15 minutes. Next, the reaction mixture was cooled to 30°-70° C. by removal of the oil bath and by blowing cool air on the flask for about 15 minutes. The reaction mixture was then filtered by suction. The pentachloronitrobenzene product in the filter cake was pressed dry and washed twice with 100 ml water each time. After drying at reduced pressure (20 tor), the product was analyzed by Vapor Phase Chromatography (VPC). In this specific example, the product was of exceptional quality with an assay of 99.20% pentachloronitrobenzene, 0.05% pentachlorobenzene and 0.37% hexachlorobenzene.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[C:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:39]3[CH2:40][CH2:41][N:36]([C:33](=[O:35])[CH3:34])[CH2:37][CH2:38]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: CC(=O)N1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCN(C(C)=O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 1-acetylpiperazine. A yellow solid 104 was obtained (0.0197 g, 41%). 1H-NMR (CDCl3, 400 MHz) δ 2.17 (s, 3H), 3.68-3.72 (m, 2H), 3.73-3.78 (m, 2H), 3.82-3.89 (m, 2H), 3.83 (s, 3H), 3.94-3.99 (m, 2H), 6.95 (s, 1H), 7.00-7.05 (m, 3H), 7.07 (d, J=8.4 Hz, 1H), 7.45-7.52 (m, 3H), 7.86 (s, 1H), 8.29 (d, J=6.2 Hz, 1H), MS (APCI) m/z 488 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.[B:14]([O:23]C(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>CCCCCC.C1COCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][B:14]([OH:23])[OH:19])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(OB(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
To a mixture of 4-bromotoluene (743 mmol) and 500 ml of THF was added dropwise 500 ml of a solution of n-butyl lithium (corresponding to 780 mmol) in hexane at −78° C. in 1.6 hours, and stirred at the same temperature for 1.5 hours. To this solution was added dropwise 200 ml of a solution of triisopropyl borate (1,486 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 750 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from about 1,000 ml of toluene to give a white solid of 4-methylphenyl boric acid (545 mmol).
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]1[CH2:33][CH2:32][C:15]2[C:16]3[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=4)=[N:20][CH:19]=[N:18][C:17]=3[S:31][C:14]=2[CH2:13]1)=[O:11])(=O)OCC)C.[H-].[Na+].CO.[CH2:38]1[CH2:42]O[CH2:40][CH2:39]1>>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:21]2[C:16]3[C:15]4[CH2:32][CH2:33][N:12]([C:10](=[O:11])/[CH:9]=[CH:9]/[CH:10]5[CH2:42][CH2:38][CH2:39][CH2:40][N:12]5[CH3:13])[CH2:13][C:14]=4[S:31][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: CCOP(=O)(CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1)OCC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CN1CCCCC1/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
In a separate flask, diethyl (2-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-7(6H)-yl}-2-oxoethyl)phosphonate from Example 13A (400 mg, 0.78 mmol) was dissolved in THF (1.0 mL). The solution was cooled to −78° C., and sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol) was added. The mixture was stirred for 15 min, then solution A was added slowly. The mixture was slowly warmed to rt and stirred overnight. Methanol was added, and the solvents were removed in vacuo. The residue was purified by preparative HPLC to yield 90 mg (24%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH:24]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:26]=[C:27]1[NH:31][C:30](=[O:32])[CH2:29][S:28]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=2)=[CH:11][C:10]=1[CH:24]=[C:29]1[S:28][C:27](=[S:26])[NH:31][C:30]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=S)N1
Reactant: CN(C)c1ccc(-c2ccc(OCc3ccccc3)c(C=O)c2)cc1
Product: CN(C)c1ccc(-c2ccc(OCc3ccccc3)c(C=C3SC(=S)NC3=O)c2)cc1
Yield: 60.1 %

Procedure:
4-Benzyloxy-4′ dimethylaminobiphenyl-3-carbaldehyde (0.1 g, 0.302 mmol) obtained in step 2) was reacted with 2-thioxo-thiazolidin-4-one (0.04 g, 0.302 mmol) in the same procedure as in step 2) of Example 1 to afford the object compound (0.081 g, 60%).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[O-]CC.[Na+].[C:10]([OH:18])(=[O:17])/[C:11](=[C:13](\[CH:15]=O)/[Br:14])/Br>C(O)C>[Br:14][C:13]1[C:11]([C:10]([OH:18])=[O:17])=[N:4][C:2]([CH3:3])=[N:5][CH:15]=1
Reactant: CC(=N)N
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc(Br)c(C(=O)O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
To a solution of acetamidine hydrochloride (6.0 g) in ethanol (20 mL) was added sodium ethoxide (20 mL of a 21% solution in ethanol) and the reaction mixture was heated at 50° C. and mucobromic acid (6.82 g) in ethanol (10 mL) was added. After stirring at 50° C. for 1 h, a further portion of sodium ethoxide (10 mL of a 21% solution in ethanol) was added and the mixture was stirred at room temperature for 16 h. The mixture was then filtered and the filtrate reduced in vacuo. The residue was then treated with 2 M aqueous hydrochloric acid (30 mL) and stirred vigorously for 30 minutes. The resulting solid was filtered, washed with water and air dried to give 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (1.46 g). This was then heated at 175° C. for 16 h. After cooling to room temperature the mixture was purified by Kugelrohr distillation to give 5-bromo-2-methyl-pyrimidine as a white solid (746 mg).
Reaction SMILES: C(OC([N:8]1[CH2:44][CH2:43][C:11]2([O:15][C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=4)=[C:30]([CH3:42])[CH:29]=3)=[N:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:45]([OH:51])([C:47](F)(F)F)=O.C(OC(=O)C)(=O)C>C(Cl)Cl.N1C=CC=CC=1>[CH3:42][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:14]4[O:15][C:11]5([CH2:43][CH2:44][N:8]([C:45](=[O:51])[CH3:47])[CH2:9][CH2:10]5)[CH2:12][N:13]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][C:35]1[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NCC6(CCN(C(=O)OC(C)(C)C)CC6)O5)cc34)cc2C)cn1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CN=C(Nc1ccc3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(C)c4)c3c1)O2

Procedure:
1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diaza-spiro[4.5]dec-2-en-8-yl)-ethanone is prepared from 2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diazaspiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride followed by standard acetylation methods using acetic anhydride in a mixture of pyridine and methylene chloride. MS ESI (+) m/z 538 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 8.68 (s, 1H), 8.28 (d, 1H), 7.83 (d, 1H), 7.64 (s, 1H), 7.52 (d, 2H), 7.48 (d, 2H), 7.12 (m, 3H), 6.93 (d, 1H), 3.69 (m, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 2.14 (s, 3H), 2.02 (m, 2H), 1.78 (m, 2H), 1.30 (m, 2H), 0.87 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O:33][C:34]([C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])C1C=CC=CC=1.C(C1C=C(NC(C2C=CC(N3CCN(C([C@H]4CCC[C@@H]4C(O)=O)=O)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:42]([CH:39]4[CH2:38][CH2:37][CH:36]([C:34]([OH:35])=[O:33])[CH2:41][CH2:40]4)=[O:43])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)cc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)[C@H]4CCC[C@@H]4C(=O)O)CC3)nc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)cc2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid was prepared from N-(3-tert-butyl-phenyl)-4-piperazin-1-yl-benzamide and trans-1,4-cyclohexane dicarboxylic acid monobenzyl ester in a manner similar to the one described in the synthesis of (1S,2S)-2-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclopentanecarboxylic acid above. HRMS m/z calcd for C29H37N3O4 [M+H]: 492.2857. Found: 492.2855.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:26]([C:36]([O:38][CH3:39])=[O:37])=[CH:25][CH:24]=1>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:27]1[C:26]([C:36]([O:38][CH3:39])=[O:37])=[CH:25][CH:24]=[C:23]([CH2:22][N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:28]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1Cl
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1Cl

Procedure:
Analogously to the preparation of Example 139, 208 mg (0.68 mmol) of the compound from Example 5A were reacted with 230 mg (0.68 mmol) of the compound from Example 109A. This gave 231 mg (59% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2]/[C:3](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].[Br:16]N1C(=O)CCC1=O>CO>[CH3:1][O:2]/[C:3](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][Br:16])=[CH:4]/[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C=C(/OC)c1ccccc1C
Solvent: CO
Product: COC(=O)/C=C(/OC)c1ccccc1CBr

Procedure:
200 g (0.97 mol) of methyl (E)-β-methoxy-2-methylcinnamate and 190 g (1.07 mol) of N-bromosuccinimide which has been washed with methanol and dried, in 2 1 of dry tetrachloromethane, are irradiated with a 300 watt UV lamp for 75 min, during which the solution begins to reflux.