Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CS(C)=O.C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]=[C:9]([C:15]([NH2:17])=[O:16])[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)c1ccccn1
Reaction time: 0.17 h

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a suspension 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (200 mg, 0.58 mmol, 1.00 equiv), 2-(pyridin-2-yl)but-3-yn-2-ol (300 mg, 2.04 mmol, 3.50 equiv) and Pd(PPh3)2Cl2 (200 mg, 0.28 mmol, 0.50 equiv) in DMSO (0.5 mL) and triethylamine (0.5 mL). The final reaction mixture was irradiated with microwave radiation for 3 h at 70° C. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 3×25 mL of water. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-016(Waters)): Column, XSelect Prep C18; mobile phase, water with 0.05% NH3H2O and CH3CN (23% CH3CN up to 63% in 10 min, hold 3 min); Detector, uv 254/220 nm. This resulted in 18 mg (7%) of 8-Fluoro-9-(3-hydroxy-3-pyridin-2-yl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a light yellow solid. LC-MS (ES, m/z): 410[M+H]+; 1H-NMR (400 MHz, DMSO-d6, ppm) δ 8.657 (d, 1H), 8.574 (d, 1H), 8.482 (s, 1H), 7.884 (m, 2H), 7.792 (d, 1H), 7.352 (m, 1H), 7.020 (d, 1H), 6.383 (s, 1H), 4.386 (t, 2H), 3.408 (t, 2H), 1.841 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:12])=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>>[CH3:11][C:9]1[NH:10][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:14]3[CH2:15][CH2:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13]3)[C:7]=2[C:8]=1[CH3:12]
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1[nH]c2ccnc(Cl)c2c1C
Product: Cc1[nH]c2ccnc(N3CCc4ccccc4C3)c2c1C
Temperature: 160 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
A mixture of 4-chloro-2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine (1.49 g, 8.25 mmol) prepared in Preparation 1 and 1,2,3,4-tetrahydroisoquinoline (4 ml) was stirred for 12 hours at 160° C. The reaction mixture was cooled to room temperature and purified with silica gel column chromatography (ethyl acetate) to give the titled compound as a white solid. (Yield: 77.1%)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([C:17](=[O:19])[CH3:18])[CH:14]=[C:13]([Cl:20])[N:12]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][C:17]([C:15]2[CH:14]=[C:13]([Cl:20])[N:12]=[C:11]([Cl:10])[CH:16]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(Cl)nc(Cl)c1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=C(CC(c1ccccc1)c1ccc(Br)cc1)c1cc(Cl)nc(Cl)c1

Procedure:
In analogy to example 11, step 1, from 4-bromobenzaldehyde and 1-[2,6-dichloropyridin-4-yl]ethanone (CAS RN: [185319-20-4]) was prepared 3-(4-bromo-phenyl)-1-(2,6-dichloro-pyridin-4-yl)-propenone as a yellow solid, which was directly subjected to the next step. In analogy to example 1, step 1, from 3-(4-bromo-phenyl)-1-(2,6-dichloro-pyridin-4-yl)-propenone and phenylboronic acid was prepared the title compound as a colorless oil, MS (EI+): m/z=433 ([M]+, 1Br, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=3)[NH:9][C:8]=2[CH3:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=3)[N:9]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:8]=2[CH3:20])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(C(F)(F)F)cc2c1Oc1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(C(F)(F)F)ccc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of the product from step (i) (0.60 g), potassium carbonate (0.516 g) and methyl bromoacetate (0.26 ml) in DMF (4 ml) was stirred at 50° C. for 4 h. The reaction was partitioned between ethylacetate/water. The organics were washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10-20% ethylacetate/iso-hexane. Yield 0.44 g
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[NH2:31][C@H:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][C@H:33]1[F:45].[Cl:46][C:47]1[N:48]=[C:49]([C:54](O)=[O:55])[NH:50][C:51]=1[CH2:52][CH3:53]>CC(N(C)C)=O.O>[Cl:46][C:47]1[N:48]=[C:49]([C:54]([NH:31][C@H:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:34][C@H:33]2[F:45])=[O:55])[NH:50][C:51]=1[CH2:52][CH3:53]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)nc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
1-Hydroxybenzotriazole hydrate (114 mg, 0.845 mmol), WSC hydrochloride (162 mg, 0.845 mmol) and triethylamine (118 μL, 0.845 mmol) were added to a solution of tert-butyl cis(±)-4-amino-3-fluoropiperidine-1-carboxylate obtained in Example (196a) (123 mg, 0.564 mmol) and 4-chloro-5-ethyl-1H-imidazole 2-carboxylic acid obtained in Example (1d) (118 mg, 0.676 mmol) in DMA (3 mL) at room temperature, and the mixture was stirred at 70° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=1:1 v/v) to obtain 159 mg of the title compound (75%) as a pale yellow foamy substance.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]([C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=3[CH:27]([CH3:29])[CH3:28])O)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>ClCCl>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=3[CH:27]([CH3:29])[CH3:28])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(Br)cc1C(O)c1ccc2c(c1)N(Cc1ccccc1)CCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)c1ccc(Br)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To an ice cold solution of (4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-(5-bromo-2-isopropyl-phenyl)-methanol (1.3 g, 2.87 mmol) in dichloromethane (25 mL) was added Et3SiH (4.8 mL, 5.70 mmol) followed by BF3.OEt2 (0.74 mL, 5.7 mmol). The reaction mixture was stirred at room temperature overnight then quenched by the addition of aq. NaHCO3. The reaction mixture was extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Crude product obtained after evaporation of the solvent was purified by silica gel column chromatography to furnish 4-Benzyl-6-(5-bromo-2-isopropyl-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (1.0 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1(C(N2C=CN=C2)=O)C=CN=C1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][NH2:33]>C1COCC1>[OH:1][C:2]1[C:3]([C:12]([NH:33][CH2:32][C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: NCc1cccs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCc1cccs1)c1ccc2cccnc2c1O
Temperature: 45 °C
Reaction time: 24 h
Yield: 53.8 %

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (100 mg, 0.53 mmol) and di(1H-imidazol-1-yl)methanone (86 mg, 0.53 mmol) in THF (8 mL) was heated to 45° C. overnight, under nitrogen. The reaction mixture was allowed to cool to RT and thiophene-2-ylmethanamine (30 mg, 0.26 mmol) was added. The resulting mixture was stirred at RT for 24 h. Additional thiophene-2-ylmethanamine (15 mg, 0.1.3 mmol) was added and the reaction mixture was stirred for 60 h at RT. The reaction mixture was quenched with H2O and THF was evaporated to dryness. Saturated solution of sodium hydrogen carbonate was added to the aqueous phase and extracted twice with DCM. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by SPE-SI cartridge (2 g, DCM to DCM:MeOH 99:1) affording the title compound (40 mg, 0.14 mmol) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:20])=[C:7]([CH2:15][CH2:16][C:17](O)=[O:18])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:6]([OH:20])=[C:7]([CH2:15][CH2:16][C:17]([Cl:23])=[O:18])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc(CCC(=O)O)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CCC(=O)Cl)c(O)c(C(C)(C)C)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Operating under a nitrogen current, 29.8 g of methyl 3-(3',5'-di-tert-butylhydroxyphenyl)propionate, 80 mL of ethanol, and 6 g of sodium hydroxide were introduced in a 0.5-L four-neck flask equipped with a stirrer, addition funnel, and thermometer and were stirred for 1 hour while heating under reflux. After completion of the stirring period, the ethanol was removed by distillation and the reaction mass was then neutralized by the gradual addition of concentrated hydrochloric acid. 150 mL of a 1:1 liquid mixture of toluene and ethyl acetate was added followed by washing twice with water. The solvent was subsequently distilled from the washed organic layer to give 27.2 g of 3-(3',5'-di-text-butylhydroxyphenyl)propionic acid in crystalline form. Then, while operating under a nitrogen current, 8.0 g of this 3-(3',5'-di-tert-butylhydroxyphenyl)propionic acid and 50 mL of dry toluene were introduced into a 0.2-L four-neck flask equipped with a stirrer, addition funnel, and thermometer and were stirred. After completion of stirring, 4 g of thionyl chloride was added dropwise at room temperature from the addition funnel. The reaction solution was then heated to 70° C. and a reaction was run for 4 hours with stirring. After completion of the reaction, the by-products were distilled under reduced pressure from the reaction solution to give 8.1 g of 3-(3',5'-di-tert-butylhydroxyphenyl)propionyl chloride in crystalline form.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[OH-].[Na+].[F:20][CH:21]([F:23])Cl>O>[F:20][CH:21]([F:23])[O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(OC(F)F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 43.0 g of 3-methyl-2-nitrophenol, 250 ml of p-dioxane, 150 ml of water, and 75 ml of 50% sodium hydroxide solution at 70° C. was added gaseous difluorochloromethane at a steady rate. The pH of the reaction was checked periodically. If the pH became acidic, 30 to 40 ml of 50% sodium hydroxide solution was added. After six hours of heating, the flow of the difluorochloromethane was halted and the reaction allowed to cool to room temperature. After standing overnight the reaction solution was poured onto a mixture of 50 g of ice and 250 ml of water and extracted with two 450 ml portions of ethyl acetate. The organic phase was dried with magnesium sulfate, filtered and concentrated. The resulting brown liquid was dried in a vacuum oven at 45° C. overnight to yield 53.3 g of the desired intermediate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:3]=1.[C:20](O)(=O)[CH2:21][SH:22].[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH:28]=O>>[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH:28]1[S:22][CH2:21][CH2:20][NH:1][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C@@H:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:3]1=2
Reactant: O=C(O)CS
Reactant: Cn1nc([C@@H]2CCCN2C(=O)OC(C)(C)C)cc1N
Reactant: O=Cc1ccc(Cl)cc1Cl
Product: Cn1nc([C@@H]2CCCN2C(=O)OC(C)(C)C)c2c1NCCSC2c1ccc(Cl)cc1Cl

Procedure:
tert-Butyl(2S)-2-[4-(2,4-dichlorophenyl)-1-methyl-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-3-yl]pyrrolidine-1-carboxylate was prepared according to procedure C using tert-butyl (2S)-2-(5-amino-1-methyl-pyrazol-3-yl)pyrrolidine-1-carboxylate, thioglycolic acid and 2,4-dichlorobenzaldehyde. The resulting amide was reduced according to procedure D and the material was used directly in Step D below.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[C:10]([O:14][C:15](=[O:36])[CH2:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:20][C:19]=1[NH2:35])([CH3:13])([CH3:12])[CH3:11]>CCO>[C:10]([O:14][C:15](=[O:36])[CH2:16][N:17]1[C:18]2[CH:23]=[CH:22][C:21]([NH:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)(=[O:27])=[O:26])=[CH:20][C:19]=2[N:35]=[C:1]1[CH2:2][CH2:3][CH3:4])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)CNc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1N
Reactant: CCCC=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Butyraldehyde (3.8 mL, 41.8 mmol) and acetic acid (1.4 mL) were added to a solution of [2-amino-4-(4-fluoro-benzenesulfonylamino)-phenylamino]-acetic acid tert-butyl ester (12.5 g, 26.8 mmol) in EtOH (135 mL), and stirred overnight at 70° C. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give the crude sub-titled compound that was used without further purification. MS calculated for C22H26FN3O4S—H: 446, observed: 446.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.[N:24]1([CH2:29][CH2:30][CH2:31]Cl)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:31][CH2:30][CH2:29][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: ClCCCN1CCCC1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCCC1
Temperature: 80 °C
Yield: 5.4 %

Procedure:
A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (1.28 g), 3-(pyrrolidin-1-yl)propyl chloride hydrochloride (Chem. Abs., 82, 57736; 1.5 g), potassium carbonate (2.8 g) and DMF (20 ml) was stirred and heated to 80° C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 20:3 mixture of methylene chloride and methanol as eluent. The material so obtained (1.1 g) was triturated under ethyl acetate to give 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-pyrrolidin-1-ylpropoxy)quinazoline (0.094 g). The organic solution was evaporated and the residual solid was recrystallised from acetonitrile. There was thus obtained a second crop (0.85 g) of the same product. The material gave the following characterising data:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: Oc1ccccc1
Product: CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N-Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].ON1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2N=N1.C([O:24][CH2:25][CH3:26])(=O)C>ClCCl>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:25](=[O:24])[CH:26]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: On1nnc2ccccc21
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
1-(3-Dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (EDC, 210 mg, 1.1 mmol, 1.2 equiv) was added to a solution of acid (190 mg, 0.91 mmol, 1.0 equiv), 4-aminoacetophenone (120 mg, 0.91 mmol, 1.0 equiv) and 1-hydroxybenzotriazole (HOBT, 190 mg, 1.4 mmol, 1.5 equiv) in dichloromethane at 23° C. The reaction mixture was stirred at 23° C. for 18 hours, diluted with ethyl acetate (50 mL), washed once with 1N sodium hydroxide (25 mL) and once with 1N hydrochloric acid (25 mL). The organics were dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (25% THF/hexanes) to provide N-(4-Acetyl-phenyl)-2,2-diphenyl-acetamide (140 mg). MS: 330 (M+1)
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[C:16]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:15]=3[CH:14]=[CH:13][N:12]4[C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=3)[CH2:23][CH2:24]2)[CH:33]=[CH:32][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: COC(=O)c1ccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)cc1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using methyl 4-iodobenzoate and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 510.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.P(Cl)(Cl)(Cl)=O.Cl[C:20]1[CH:25]=[CH:24][C:23](S)=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].Cl.[CH2:32]([OH:34])C>C(OCC)C>[CH:20]1([CH:32]([OH:34])[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH2:3][N:2]([CH3:13])[CH3:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCO
Reactant: Sc1ccc(Cl)cc1
Reactant: CN(C)C=CC(=O)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 35, but starting from 3-dimethylaminoacrylophenone (5 g), phosphorus oxychloride (2.5 cc), p-chlorothiophenol (4.13 g) and sodium cyanoborohydride (1 g), and after evaporating the reaction mixture under reduced pressure (2.7 kPa) at 40° C., a residue is obtained, which is dissolved in ethanol (50 cc). A 3N solution (12 cc) of hydrochloric acid gas in ethyl ether is added to this solution. The precipitate formed is separated off by filtration and then recrystallised from ethanol (70 cc). In this way 3-(4-chlorophenylthio)-1-dimethylamino-3-phenylthio-2-propene (Z) hydrochloride (3.4 g) is obtained in the form of a white powder melting at 226° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C>Cl.O=[Pt]=O.C(Cl)(Cl)Cl>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(OCCN2CCOCC2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NCc1ccc(OCCN2CCOCC2)cc1
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of 4-[2-(4-morpholinyl)ethoxy]benzonitrile (0.93 g, 4 mmol), ethanol (100 mL), CHCl3 (4 mL) and PtO2 (100 mg) was hydrogenated at 45 psi on a Parr hydrogenator for 8 hours. Concentrated HCl (2-3 drops) was then added to the reaction mixture and the hydrogenation was continued for another 10 hours. The catalyst was removed by filtration, the filter cake was washed with ethanol and then the filtrate was evaporated to dryness. The residue was dissolved in water and then was saturated with solid K2CO3. The mixture was extracted with CH2Cl2 and then the CH2Cl2 layer was dried over K2CO3 and evaporated to afford 0.75 g (79%) of 4-[2-(4-morpholinyl)ethoxy]phenylmethylamine.
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl.[NH4+].[Cl-]>ClCCl>[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25][O:1][C:2]1([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: OC1(c2nccs2)CCC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCOC1(c2nccs2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
To a solution of the alcohol 2-[(1-Hydroxy)cyclobutyl]thiazole from Step 1 (5 g, 32 mmol) and Hunig's base (10.4 mL, 60 mmol) in dichloromethane (100 mL) at 0° C. was added 2-(trimethylsilyl)ethoxymethyl chloride (6.5 mL, 36.7 mmol). The resulting solution was stirred at 0° C. for 1 h, was heated at reflux temperature for 3.5 h and finally was stirred at room temperature for 15 h. Sat. aq. NH4Cl was added and the resulting mixture was extracted with dichloromethane (3×). The combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of-the residue (silica gel; dichloromethane to dichloromethane/ethyl acetate 95:5) provided 2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclobutyl}thiazole (2 g).