Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1.C(N(CC)CC)C.[Cl:26][C:27]([Cl:33])=[C:28]([Cl:32])[C:29](Cl)=[O:30].O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([O:7][C:29](=[O:30])[C:28]([Cl:32])=[C:27]([Cl:33])[Cl:26])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(OC(=O)C(Cl)=C(Cl)Cl)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 74.6 %

Procedure:
2.85 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxy pyrazole and 1.01 g of triethylamine were dissolved in 20 ml of benzene. 1.94 g of trichloroacrylic acid chloride were dropped into the solution. The reaction mixture was stirred for 3 hours at the reflux temperature of benzene. After the completion of the reaction, water was added to the reaction mixture, the organic layer was separated and dried. Benzene was distilled off under reduced pressure to give 3.3 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-trichloroacryloyloxy pyrazole as colorless crystals of melting point 141° to 142° C.
Reaction SMILES: [OH:1][C:2]([CH2:10][CH2:11][CH3:12])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.[CH3:18][Si:19]([CH3:22])([CH3:21])Cl.CCOCC>CN(C)C=O.O>[CH3:18][Si:19]([CH3:22])([CH3:21])[O:1][C:2]([CH2:10][CH2:11][CH3:12])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CCC)CCCC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: C#CCC(CCC)(CCCC)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.8 Grams of 4-hydroxy-4-n-propyl-1-octyne is dissolved in 100 ml of dimethylformamide and treated with 8 g of imidazole and then with 12 g of trimethylchlorosilane. The reaction mixture was stirred at room temperature for 1 hour and then poured into a mixture of ether and water. The organic layer was washed with water 3-4 times, dried over sodium sulfate, and stripped of solvent. Distillation of the residue gave the title product as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[C:13]([O:16][C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(Cl)Cl.N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[C:13]([O:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:28](=[O:30])[CH3:29])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCNC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline (0.22 g, 0.51 mmole) (prepared as described in Example 29-preparation of starting materials) was dissolved in a mixture of methylene chloride (4 ml), pyridine (1 ml) and diisopropylethylamine (0.17 ml) under a nitrogen atmosphere. Acetic anhydride (0.1 ml, 1.0 mmole) was added and the mixture stirred at ambient temperature for 3 hours. The mixture was then partitioned between saturated aqueous NaHCO3 and ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The fractions containing the expected product were evaporated and triturated with diethylether. The solid was filtered and dried under vacuum to give the title product as a white solid (0.12 g: 55%); 1H NMR Spectrum: (DMSO d6) 1.95-1.98 (m, 3H); 2.14-2.40 (m, 2H); 3.53-3.70 (m, 3H); 3.91 (m, 4H); 5.12-5.21 (m, 1H); 7.15-7.30 (m, 2H); 7.4-7.60 (m, 2H); 7.70-7.90 (m, 1H); 8.36-8.37 (d, 1H); 9.60-9.62 (m, 1H); Mass Spectrum: (M+H)+ 431.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1>CN(C=O)C>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ncnc(Cl)c2c1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: COc1ccc2ncnc(N3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Piperazine (1.1 g, 12.8 mmol) was added to a solution of 4-chloro-6-methoxy-quinazoline (0.5 g, 2.6 mmol) in DMF (5 mL). The mixture was stirred at rt for 1 h, partitioned between chloroform and aq. ammonia. The org. phase was washed with water, dried over MgSO4 and concentrated. Purification by CC (DCM/MeOH 19:1+0.5% NH4OH) gave the desired intermediate (0.57 g, 91%) as yellow oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][C@@H:30]([CH3:34])[C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[C@@H:30]([O:29][CH3:28])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CO[C@@H](C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CO[C@@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (63 mg, 61%), MS (ISP) m/z=417.4 [(M+H)+], mp 158.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (S)-2-methoxy-propanoic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: Clc1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N)c2c(OCC3CCN(Cc4cccc(Cl)c4)CC3)cccc2n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (2.5 g, 9.15 mmol) and diisopropylethylamine (2.96 g, 22.87 mmol) in DMF (16 mL) was added a solution of 3-chlorobenzyl bromide in DMF (4 mL). The reaction mixture was heated at 60° C. with stirring for 20 h. The mixture was concentrated, water was added stirred for 1 h. The precipitate was filtered, washed with water, dried. Purified by silica gel column chromatography using 3-10% methanol in dichloromethane afforded 1.82 g of 5-[1-(3-chlorobenzyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine 1H NMR (400 MHz, DMSO-d6) δ 7.25-7.38 (m, 5H), 7.2 (s, 2H), 6.77 (dd, J=8.0, 1.2 Hz, 1H), 6.53 (dd, J=8.0, 0.8 Hz, 1H), 5.95 (s, 2H), 3.99 (d, J=6.4 Hz, 2H), 3.48 (s, 2H), 2.84 (d, J=11.2 Hz, 2H), 1.7-2.07 (m, 5H), 1.3-1.42 9m, 2H). MS m/z (ESI) 399 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Pd]>[CH2:5]([NH:3][CH2:2][CH2:1][NH2:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: NCCN
Agent: [Pd]
Product: NCCNCc1ccccc1

Procedure:
Benzylethylenediamine (Bz-EDA) was prepared by placing 250 g of ethylenediamine (4.16 moles) and 2.5 g of 5% Pd/C catalysts were placed in a stainless steel reactor under hydrogen pressure (800 psig) at 120° C. Benzaldehyde (441.7 g, 4.16 moles) were pumped inside the reactor over a period of an hour. The reaction was allowed to proceed for an extra hour. The reactor was then cooled down, the catalyst was removed by filtration to give the corresponding product.
Reaction SMILES: Cl[CH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].C([SnH](CCCC)CCCC)CCC>>[F:6][C:5]([F:7])=[C:4]([F:8])[CH2:3][CH2:2][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCC(Cl)CC(F)=C(F)F
Agent: CCCC[SnH](CCCC)CCCC
Product: CCCCCCCCCCC(F)=C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 4.6 grams (0.0179 mole) of 4-chloro-1,1,2-trifluoro-1-dodecene (prepared as in Example 7) and 0.04 gram (0.0003 mole) of alpha, alpha-azobisisobutyronitrile is flushed with argon and 5.1 ml (0.019 mole) of tri-n-butyltin hydride is added dropwise. Upon completion of addition, the reaction mixture is stirred at ambient temperature for 16 hours. The reaction mixture is fractionally distilled under reduced pressure through a Vigreux column. The appropriate fractions are recombined and redistilled, again under reduced pressure and through a Vigreux column. The yield of 1,1,2-trifluoro-1-dodecene is 1.2 grams; b.p. 42°-45° C./0.45mm. The nmr spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: FC(F)(F)CCBr
Reactant: N#Cc1ccc(CC(C#N)C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 27.4 %

Procedure:
Using 1.00 g of (4-cyanobenzyl)malononitrile, 10 ml of N,N-dimethylformamide, 0.36 g of sodium hydride (60% in oil), and 2.37 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.42 g of 2-(4-cyanobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (22)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Li]C(C)(C)C.[Si:14]([O:21][CH2:22][CH:23]=[N:24][S@@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[Li]>CCOCC>[Si:14]([O:21][CH2:22][C@H:23]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@@](=O)N=CCO[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc(Br)nc1
Agent: [Li]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)S(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cn1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a cold solution of 2-bromo-5-fluoropyridine (1.3 g, 7.2 mmol) in Et2O (8 ml) at −68° C. was added a solution of t-BuLi (1.7 M in pentane, 8.5 ml, 14.4 mmol) carefully. The temperature of the mixture was kept below −65° C. and the mixture was allowed to stir for 15 minutes at −70° C. A solution of (R)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene)-2-methylpropane-2-sulfinamide (Intermediate 21, 1.0 g, 3.6 mmol) in Et2O (24 ml) was cooled to −75° C. To it was cannulated a solution of the above lithium compound for a duration of 15 minutes. More Et2O (2 ml) was used to rinse the lithium compound solution. The mixture was allowed to stir at −78° C. for 3 hours. To it was added saturated NH4Cl solution. EtOAc was added and the organic layer was washed with brine and concentrated. Column chromatography (20-40% EtOAc in hexanes) gave the desired product (RS)—N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide* as a solid (higher Rf on TLC, 1.19 g) together with diastereoisomer (lower Rf on TLC, 166 mg). 1H NMR (300 MHz, CDCl3) □ ppm 8.41 (s, 1H) 7.35 (d, J=6.78 Hz, 2H) 4.59 (t, J=5.65 Hz, 1H) 4.43 (d, J=5.28 Hz, 1H) 3.82-4.02 (m, 2H) 1.23 (s, 9H) 0.81 (s, 9H)-0.06 (d, J=12.06 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccc(F)cc1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(F)cc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=294.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-4-fluoro-benzene.
Reaction SMILES: [I-].[I:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:33]([C:35]([CH3:40])([CH2:38][CH3:39])[CH:36]=O)[CH3:34]>O1CCCC1>[CH2:33]([C:35]([CH3:40])([CH2:38][CH3:39])/[CH:36]=[CH:3]\[I:2])[CH3:34]
Reactant: IC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(C)(C=O)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(/C=C\I)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A suspension of (iodomethyl)triphenylphosphonium iodide (0.530 g, 1 mmol) in tetrahydrofuran (3 mL) was treated dropwise at room temperature with sodium bis(trimethylsilyl)amide (1 mL, 1M solution in THF, 1 mmol) for 2-3 minutes. The solution was then cooled to −78° C. and a solution of 2-ethyl-2-methyl-butanal (0.100 g, 0.88 mmol) in tetrahydrofuran was added dropwise. The cooling bath was removed and stirring continued at room temperature for 1 hour. The reaction mixture was diluted with hexane, filtered and evaporated. The crude compound was purified by silica gel chromatography (hexane) and afforded the title compound (0.130 g, 62%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:17][N:18]1[C@@H:23]2[C@@H:24]3[O:26][C@@H:25]3[C@H:19]1[CH2:20]C(O)[CH2:22]2.[Na].Cl>C1(C)C=CC=CC=1>[CH3:17][N:18]1[C@@H:23]2[C@@H:24]3[O:26][C@@H:25]3[C@H:19]1[CH2:20][CH:10]([O:9][C:7]([C:6]([OH:11])([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:22]2
Reactant: CN1[C@@H]2CC(O)C[C@H]1[C@@H]1O[C@@H]12
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1[C@@H]2CC(OC(=O)C(O)(c3cccs3)c3cccs3)C[C@H]1[C@@H]1O[C@@H]12
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
38.15 g (0.15 mole) of methyl di-(2-thienyl)glycolate and 23.28 g (0.15 mole) of scopine are mixed, 0.34 g (0.015 gram atom) of sodium is added and the mixture is melted in a heating bath at 90° C. under a water jet vacuum. The reaction lasts 2.5 hours. 100 ml of absolute toluene are then added and the mixture is stirred at a heating bath temperature of 90° C. until a solution is produced. The reaction solution is cooled to room temperature and stirred into a mixture of ice and hydrochloric acid cooled using ice. The hydrochloride of the basic ester crystallising out is filtered off under suction and washed using a small amount of water and a large amount of diethyl ether. The filtrate phases are separated off and the aqueous phase is extracted using diethyl ether. The hydrochloride filtered off under suction is suspended in the (acid) aqueous phase and converted to the base while monitoring the temperature and adding the corresponding amount of sodium carbonate; the base is extracted using methylene chloride. The combined methylene chloride phases are dried over sodium sulphate. After distilling off the methylene chloride, crystals remain which are purified over active charcoal and recrystallised from acetonitrile. Pale yellow crystals (from acetonitrile), m.p. 148°-49° C.;
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][C:3]=1[F:26].[CH3:27][N:28]([CH3:40])[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)=[O:30]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=4)[C:29]([N:28]([CH3:40])[CH3:27])=[O:30])=[C:3]([F:26])[CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Reactant: CN1CCN(c2cc(N3CCc4cc(F)c(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4cc(F)c(-c5cccc(C(=O)N(C)C)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 127 starting from 4-(7-bromo-6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and {3-[(dimethylamino)carbonyl]phenyl}boronic acid (Frontier, Cat. No. D4088). LCMS (M+H)+: m/z=490.2.
Reaction SMILES: [C:1]1([C:7]([OH:15])([C:11]([NH:13][NH2:14])=[O:12])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]([CH3:19])=O>>[CH3:16][C:17](=[N:14][NH:13][C:11](=[O:12])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:15])[C:8]([NH2:10])=[O:9])[CH3:19]
Reactant: NNC(=O)C(O)(C(N)=O)c1ccccc1
Reactant: CC(C)=O
Product: CC(C)=NNC(=O)C(O)(C(N)=O)c1ccccc1

Procedure:
20 g of phenylhydroxymalonic acid amide-hydrazide in 100 ml of acetone were heated under reflux for 3 hours. The crystals were filtered off with suction and recrystallised from ethanol. 15 g of phenylhydroxymalonic acid amide-(2-propylidene)-hydrazide (melting point: 199°-201° C.) were obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])(Cl)Cl.Cl.[OH2:16]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])=[O:16]
Reactant: O
Reactant: Fc1cc(C(Cl)(Cl)Cl)c(F)c(F)c1F
Agent: Cl
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Yield: 89.3 %

Procedure:
802 g of 2,3,4,5-tetrafluoro-benzotrichloride are initially introduced into a stirred apparatus, and 8 g of FeCl3 are added. Water is slowly metered in under the surface of the starting material at 120° C. (54 g of water in total). Vigorous evolution of hydrogen chloride immediately starts. The hydrogen chloride is passed to a destruction tower via the condenser. The mixture is stirred until the evolution of gas has ended. The product is then distilled. 569 g of 2,3,4,5-tetrafluoro-benzoyl chloride are obtained (89.4% of theory), boiling point: 80-82° C./18 mbar.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[C:21]=1[O:22]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([O:24][C:25]([F:28])([F:26])[F:27])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:17])(=[O:18])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1OC(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(OC(F)(F)F)c1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
3-(3-cyano-4-methoxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (300 mg) was dissolved in N,N-dimethylformamide (4 mL), and lithium chloride (309 mg) was added to the solution, and then the mixture was stirred at 100° C. for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (184 mg) as a colorless crystal.
Reaction SMILES: Cl.Cl[C:3]1C=C(NN)C=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:23]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26](Cl)[CH:25]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:20]2)[CH:15]=[CH:16][C:17]=1F>>[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:23]([C:24]3[CH:25]=[C:26]([CH3:3])[CH:27]=[C:28]([F:30])[CH:29]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:20]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cc(C)cc(F)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 20A and 3-chlorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 1.75 g of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[S:12][C:13]=2[CH:14]([NH:16]S(C(C)(C)C)=O)[CH3:15])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[S:12][C:13]=2[CH:14]([NH2:16])[CH3:15])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(NS(=O)C(C)(C)C)c1sc2ccccc2c1-c1cc(F)cc(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(N)c1sc2ccccc2c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(1-(3-(3,5-difluorophenyl)benzo[b]thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (392 mg, 0.996 mmol) in THF (7 mL) at rt was added HCl (1.0 mL, 11.85 mmol). The reaction was stirred at ambient temperature for 10 min, after which time LC-MS indicated no starting material remained. The reaction was poured into satd. aq. NaHCO3 and extracted two times with EtOAc. The combined organic extracts were stirred over MgSO4, filtered and concentrated under reduced pressure to give 1-(3-(3,5-difluorophenyl)benzo[b]thiophen-2-yl)ethanamine as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 1.35 (d, J=6.7 Hz, 3H), 1.60 (br. s., 2H), 4.39 (q, J=6.6 Hz, 1H), 6.73-6.86 (m, 3H), 7.19-7.24 (m, 2H), 7.30-7.36 (m, 1H), 7.71-7.77 (m, 1H); LC-MS (ESI)] m/z 273.0 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:9]=1[OH:16].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:16][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[C:13]([F:14])[C:8]=1[F:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccc(F)c(F)c1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Fc1ccc(OCc2ccccc2)c(F)c1F
Temperature: 50 °C
Yield: 90.8 %

Procedure:
Sodium carbonate (19.50 g, 0.184 mol) was dispersed into a solution of 2,3,4-trifluorophenol (13.64 g, 0.092 mol) in acetone (300 mL). To the stirred suspension was added the solution of benzyl bromide (17.31 g, 101.21 mmol) in acetone (100 mL) dropwisely. The mixture was heated under reflux at 50° C. for 24 h, allowed to cool to room temperature, and filtered. The filter cake was washed with acetone (50 mL×3), and acetone was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL). The solution was washed with 5% sodium hydroxide (50 mL), water (150 mL) and brine (150 mL) sequentially and dried over Na2SO4. The solvent was removed in vacuo to yield a pale yellow solid (19.89 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 7.40 (m, 5H), 6.85 (m, 1H), 6.64 (m, 1H), 5.15 (s, 2H).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C@@H:28]([NH2:31])[CH2:29][OH:30])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C@@H:28]([NH:31][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:29][OH:30])=[CH:25][CH:26]=1
Reactant: N[C@@H](CO)Cc1ccc(F)cc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)Cc2ccc(F)cc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
The similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-2-(4-fluoro-phenyl)-1-hydroxymethyl-ethylamine and DIEA to give 2-[(R)-2-(4-fluoro-phenyl)-1-hydroxymethyl-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 408 (MH+).