Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH2:30])[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1nc(-c2ccc3cnccc3c2)no1)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CCc1nc(-c2ccc3cnccc3c2)no1)Cc1ccc(C(F)(F)F)cc1

Procedure:
tert-Butyl(R)-4-(3-(isoquinolin-6-yl)-1,2,4-oxadiazol-5-yl)-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (0.016 g, 0.03 mmol) was treated with TFA (1 mL, 13 mmol) in 1 mL DCM for 1 hour. After removing the solvent and making the remaining residue basic with 2M ammonia in MeOH, the residue was subjected to a silica gel plug using 3% 2M ammonia in MeOH in DCM as the eluant to yield an off-white solid as the desired product. LCMS (API-ES) m/z (%): 413.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 2.07-2.18 (m, 1H) 2.22 (s, 1H) 2.95-3.03 (m, 1H) 3.05-3.13 (m, 1H) 3.17-3.28 (m, 2H) 3.48-3.58 (m, 1H) 7.52 (d, J=7.53 Hz, 2H) 7.68 (d, J=8.03 Hz, 2H) 7.95 (d, J=5.52 Hz, 1H) 8.23-8.31 (m, 2H) 8.54 (d, J=6.02 Hz, 1H) 8.64 (s, 1H) 9.33 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24](=O)[CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:37][N:38]([CH2:40][CH2:41][NH:42][C:43]([NH2:45])=[S:44])[CH3:39]>C(O)C>[CH3:37][N:38]([CH3:39])[CH2:40][CH2:41][NH:42][C:43]1[S:44][C:23]2[CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:13][CH:14]=3)=[O:19])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]=2[N:45]=1
Reactant: CN(C)CCNC(N)=S
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: CCO
Product: CN(C)CCNc1nc2c(s1)CCN(C(=O)c1ccc(NC(=O)c3ccccc3-c3ccccc3)cc1)c1ccccc1-2
Yield: 58.8 %

Procedure:
Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro1H-1-benzazepin-1-yl)carbonyl]benzanilide and 300 mg of dimethylaminoethylthiourea hydrochloride and using ethyl alcohol as the reaction solvent, the procedure of Example 5 was repeated and the resulting residue was recrystallized from ethyl acetate-diethyl ether to obtain 300 mg of 4'-[(2-dimethylaminoethylamino-5,6-dihydro-4H-thiazolo[5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide.2 HCl.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].Cl>CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([NH2:20])[CH3:19])=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C#Cc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOc1ccc(C#Cc2ccc(C(C)N)cc2)cc1
Temperature: 25 °C

Procedure:
To 25.0 g (62.90 mmol) tert-butyl 1-(4-((4-ethoxyphenyl)ethynyl)phenyl)ethyl-carbamate (I62) in 375 mL EtOAc are added 79 mL (315 mmol) HCl (4M in dioxane). The mixture is stirred at r.t. over night, filtered and the obtained precipitate is dried. The crude product is suspended in DCM and sat. NaHCO3 is added until a clear solution is obtained. The layers are separated and the aqueous layer is extracted two more times with DCM. The organic layers are combined, washed with brine (1×), dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, heptane/EtOAc/TEA 75/25/1→0/100/1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][N:9]([CH2:13][C:14]1[S:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[C:10]([NH2:12])=[S:11])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1)=O>CO>[C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][N:9]([C:10]1[S:11][CH:22]=[C:23]([C@H:25]2[CH2:26][CH2:27][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:29][CH2:30]2)[N:12]=1)[CH2:13][C:14]1[S:15][C:16]([CH3:19])=[CH:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)CBr)CC1
Reactant: Cc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Solvent: CO
Product: Cc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc([C@H]3CC[C@H](C(C)(C)C)CC3)cs2)s1

Procedure:
3-[1-(5-methyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (100 mg, 0.318 mmol) in MeOH (about 4 mL) was treated with two portions of 2-Bromo-1-(trans-4-tert-butyl-cyclohexyl)-ethanone (2×83 mg, 2×0.318 mmol) (second addition spaced at an interval of 2 hours after first portion) at 60° C. following a method analogous to General Procedure C to produce 3-[[4-(trans-4-tert-Butyl-cyclohexyl)-thiazol-2-yl]-(5-methyl-thiophen-2-ylmethyl)-amino]propionic acid tert-butyl ester (158 mg). which was isolated by a workup that included evaporation of the solvent and partitioning the resulting material between EtOAc and saturated aq sodium bicarbonate solution. Extraction of the aq sodium bicarbonate layer with EtOAc (2 times), drying the combined organic portion over sodium sulfate and evaporation of the solvent gave the crude material which was purified using silica gel chromatography (eluent hexanes→19:1 ethyl acetate:hexanes→9:1 ethyl acetate:hexanes).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][CH2:21][CH2:22][C:23]#[CH:24]>>[CH3:19][O:20][CH2:21][CH2:22][C:23]#[C:24][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCOC
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(Br)c1
Product: COCCC#Cc1cccc(CCCNC(=O)OC(C)(C)C)c1

Procedure:
Sonogashira reaction of bromide 57 with 4-methoxybut-1-yne gave tert-butyl 3-(3-(4-methoxybut-1-ynyl)phenyl)propylcarbamate as yellow oil. Yield (0.83 g, 77%): 1H NMR (400 MHz, CDCl3) δ 7.22-7.25 (m, 2H), 7.16-7.21 (m, 1H), 7.09 (d, J=7.6 Hz, 1H), 4.51 (bs, 1H), 3.60 (t, J=7.8 Hz, 2H), 3.41 (s, 3H), 3.10-3.16 (m, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 1.76-1.84 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[I:10]I>[NH4+].[OH-].O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:10]
Reactant: II
Reactant: N#Cc1ccc(O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: N#Cc1ccc(O)c(I)c1
Reaction time: 6 h
Yield: 80.1 %

Procedure:
To a solution of 4-hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of I2 (1.06 g; 4.18 mmol) and KI (3.41 g; 20.54 mmol) in H2O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H2O (3 ml). The precipitate formed was filtered off, washed with cold H2O (3×2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1H-NMR (CDCl3) 7.96 (d, 1H, 1.9 Hz); 7.53 (dd, 1H, J=1.9 Hz, 8.5 Hz); 7.03 (d, 1H, J=8.5 Hz); 6.03 (s, 1H);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH:21]1[CH2:23][CH:22]1[C:24]([O:26]CC)=[O:25])=[CH:15]2.[OH-].[Na+].Cl.[CH3:32]O>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C@@H:21]1[CH2:32][C@H:23]1[CH2:22][C:24]([OH:26])=[O:25])=[CH:15]2
Reactant: CO
Reactant: CCOC(=O)C1CC1c1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C[C@@H]1C[C@H]1c1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Ethyl 2-{5-[3-(2-pyridylamino)propoxy]indolyl}cyclopropanecarboxylate (0.38 g, 1.056 mmol), as prepared in the preceding step, was dissolved in 7.5 mL of methanol. A solution of NaOH (0.13 g, 3.18 mmol) in water (2.5 mL) was added and the reaction was stirred at ambient temperature overnight. The base was then neutralized with an aqueous solution of HCl (3.18 mmol), and the solvent was evaporated under vacuum. The crude product was chromatographed on silica gel to obtain the title compound (200 mg, 57%). 1H NMR (400 MHz, CDCl3) 5 1.66 (m, 2H), 2.00 (m, 1H), 2.16 (m, 2H), 3.58 (m, 2H), 3.72 (m, 1H), 4.12 (t, 2H, J=5.8 Hz), 6.31 (dd, 1H, J=0.7, 3.2 Hz), 6.77 (m, 1H,), 6.85 (dd, 1H, J=2.3, 8.8 Hz), 6.97 (d, 1H, J=9.0 Hz), 7.06 (d, 1H, J=2.3 Hz), 7.13 (d, 1H, J=3.2 Hz), 7.33 (d, 1H, J=8.8 Hz), 7.77 (m, 2H). Mass spectrum (LCMS, ESI pos.) Calcd. for C21H23N3O3 352.2 (M+H); Found: 352.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[N:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14](Br)(Br)[C:13]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[N:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(n1)C(Br)(Br)C(=O)N2CCCOCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc2c(n1)CC(=O)N2CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under argon and at room temperature, 1.10 g (16.8 mmol) of powdered zinc are added in portions to 789 mg (1.68 mmol) of the compound obtained in Step B dissolved in 15 ml of acetic acid. After 5 hours' stirring at room temperature, the reaction mixture is filtered using a Büchner funnel, evaporated to dryness and then coevaporated in the presence of toluene. The residue, which is taken up in ethyl acetate, is washed several times with water. The organic phase is dried over magnesium sulphate, filtered and concentrated and then purified by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate, 1:1) to yield the title compound in the form of an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[F:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[C:16]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>O1CCCC1>[CH3:12][CH:10]([CH3:11])[CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:22]([C:16]1[C:17]([CH3:21])=[N:18][N:19]([CH3:20])[C:15]=1[F:14])=[O:23])=[O:13]
Reactant: CC(C)CC(=O)c1ccccc1N
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(=O)CC(C)C
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
At room temperature, 355.0 mg (2.0 mmol) of 1-(2-aminophenyl)-3-methylbutan-1-one are added to a solution comprising 388.5 mg (2.2 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride and 0.45 ml (3.2 mmol) of triethylamine in 20 ml of tetrahydrofuran. The reaction mixture is stirred at 60° C. for 1.5 h, filtered through silica gel and concentrated. Column chromatography (cyclohexane/ethyl acetate: 3/1) gives 577.7 mg (1.8 mmol, 88% of theory) of N-[2-(3-methylbutyryl)phenyl-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide of logP (pH=2.3)=3.42.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6]C1C=C(C=CC=1)C(O[CH:13]1[C:18](=[O:19])[NH:17][C:16]([CH3:20])=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[S:14]1)=O.Cl>ClCCl.CO>[ClH:6].[CH2:1]([N:3]([CH2:4][CH3:5])[CH:13]1[C:18](=[O:19])[NH:17][C:16]([CH3:20])=[C:15]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[S:14]1)[CH3:2]
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Reactant: CCNCC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)C1SC(c2ccncc2)=C(C)NC1=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 78.4 %

Procedure:
Diethylamine (2.58 ml) was added to a solution of 2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (0.9 g) in dry dichloromethane (12 ml) and the mixture was stirred at ambient temperature for 21 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, was washed with saturated sodium bicarbonate aqueous solution and successively with water and was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (Wakogel C-200) column, using chloroform-methanol (=20:1) as an eluant to give pale yellow oily product. The oily product was dissolved in methanol and was adjusted to pH 2 by 2N hydrochloric acid. The solvent was removed under reduced pressure and the residue was washed with THF and allowed to stand to give the titled compound (0.685 g, yield 78.4%) as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH2:36])[NH:34][N:35]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH:36][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:18][CH:17]=3)[NH:34][N:35]=2)[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCCN(C)CC2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 20.4 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide was prepared following the procedure as for Example 115, but starting from of methyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate (0.372 g, 1.5 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.371 g, 1.5 mmol) and 2M trimethylaluminium in toluene (1.875 ml, 3.75 mmol). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% 2.5M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness and the residual oil crystallised from DCM/diethyl ether to afford the title compound (0.142 g, 20.42%) as a white solid. 1HNMR (500.13 MHz, DMSO-d6+CD3COOD@373K) δ: 2.08-2.15 (2H, m), 2.69 (3H, s), 2.88 (4H, s), 3.11 (2H, t), 3.19-3.24 (2H, m), 3.56 (2H, t), 3.72 (3H, s), 3.74 (2H, t), 6.30 (1H, d), 3.32 (1H,$), 6.49 (2H, s), 6.79 (2H, d), 7.86 (2H, d). MS: m/z 464 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)C(C)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.0 g, 8.4 mmole) and ethyl 2-bromopropanoate (1.52 g, 8.4 mmole) in tetrahydrofuran (50 ml) was added triethylamine (0.85 g, 8.4 mmole) The mixture was stirred at room temperature for 20 hours. Solids were removed by filtration and the filtrate was added to diethyl ether (75 ml) and then washed with 1 N hydrochloric acid (50 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]1.[H][H]>[Ni].O1CCCC1>[O:19]=[S:15]1(=[O:18])[CH2:16][CH2:17][N:12]([C:3]2[C:4]([F:11])=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[F:1])[CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1

Procedure:
To an autoclave is added 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine 1,1-dioxide (Step 2, 7.0 kg, 24 moles, 1.0 eq). Raney Nickel (1.4 kg) is activated and suspended in tetrahydrofuran (4 L), and the slurry is added to the autoclave followed by additional tetrahydrofuran (66 L). The mixture is heated at 40° C. under a 40 psi hydrogen atmosphere until the reaction is complete. The mixture is then filtered, and the filtrate is directly used in the next step. A small portion of the filtrate can be concentrated and recrystallized in isopropanol to give the title compound in pure form, 1H NMR (DMSO-d,) δ 6.17 (m, 2H), 5.35 (s, 2H), 3.32 (m, 4H), 3.15 (m, 4H).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4]1.[C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24](F)=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1)#[CH:10]>C1COCC1>[C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:8][C@H:5]4[CH2:6][CH2:7][O:3][CH2:4]4)=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1)#[CH:10]
Reactant: O[C@H]1CCOC1
Reactant: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#Cc1cccc(Nc2ncnc3cc(O[C@H]4CCOC4)c([N+](=O)[O-])cc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48370.9 %

Procedure:
In an ice bath, NaH (1.87 g, 60%, 0.046 mol) was carefully added into a solution of (S)-tetrahydrofuran-3-ol (3.43 g, 0.039 mmol) in 100 mL anhydrous THF, and stirred for 2 hours at room temperature. Then N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine (10 g, 0.032 mol) was added and stirred for at 60° C. overnight. The solution was quenched with 1 mL H2O and concentrated, the residue was purified by silica gel column to give (S)—N-(3-ethynylphenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine as yellow solid 7.1 g (58.1% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][C:38]([NH:41][S:42]([C:45]1[S:49][C:48](Br)=[CH:47][CH:46]=1)(=[O:44])=[O:43])([CH3:40])[CH3:39].CCCCCC>C1(C)C=CC=CC=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>[C:38]([NH:41][S:42]([C:45]1[S:49][C:48]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=3)[CH:23]=2)=[CH:47][CH:46]=1)(=[O:43])=[O:44])([CH3:40])([CH3:37])[CH3:39]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)c(F)c3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.9 %

Procedure:
A stirred mixture of 4-(3,4-difluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.13) (0.21 g, 0.34 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.11 g, 0.37 mmol), tetrakis(triphenylphosphine)palladium (0.024 g, 0.02 mmol) in toluene (3 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=O.[Cl:12][C:13]1C=C(Cl)[N:16]=[CH:15][N:14]=1.CO>O1CCOCC1>[Cl:12][C:13]1[CH:7]=[C:5]([CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])[N:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)Cc1cc(Cl)ncn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2.7 g (50 mmol) of sodium hydride (80% dispersion in oil) were placed in 100 ml of dry dioxane, and 11.7 g (90 mmol) of ethyl acetoacetate were added dropwise. The mixture was then stirred at 50° C. for 1 hour. After cooling to room temperature, a solution of 4.5 g (30 mmol) of 4,6-dichloropyrimidine in 50 ml of dioxane was added dropwise. After heating at reflux for 6 hours the mixture was cooled to room temperature, 10 ml of methanol were added dropwise in order to destroy superfluous sodium hydride, and the mixture was concentrated. The residue was taken up in water and brought to a pH of 3 to 4 with conc. hydrochloric acid. After extractive stirring with toluene, the organic phase was dried and concentrated. Chromatography on silica gel left 1.8 g (30% of theory) of a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:11]([N:15]=[C:16]=[S:17])([CH3:14])([CH3:13])[CH3:12]>C(O)C.C(OCC)(=O)C>[C:11]([NH:15][C:16]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])=[S:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)c1ccccc1

Procedure:
N-(tert-Butyl)-N′-[(1R)-2-hydroxy-1-phenylethyllthiourea: The process is performed under the conditions of Example 1, starting with 2.74 g of (R)-(−)-2-amino-2-phenylethanol and 2.8 cm3 of tert-butyl isothiocyanate in 15 cm3 of ethanol for 20 hours at a temperature in the region of 20° C. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. A yellow oil is obtained, which is dissolved in 100 cm3 of ethyl acetate and the organic solution is then washed with twice 50 cm3 of aqueous sodium hydrogen carbonate solution and twice with aqueous sodium chloride solution. After drying over sodium sulfate, the organic solution is filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 4.9 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-phenylethyl]thiourea are obtained in the form of a yellow solid melting at 98° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Br:14]Br>CCOCC>[Br:14][CH:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=2[C:10]1=[O:11]
Reactant: BrBr
Reactant: O=C1CCCOc2ccc(Br)cc21
Solvent: CCOCC
Product: O=C1c2cc(Br)ccc2OCCC1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3 g, 12 mmol) in ether (110 mL) was added bromine (0.7 mL, 14 mmol) and allowed to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified via ISCO chromatography (hexane to 20% hexane in EtOAc over 45 minutes). Collected fractions and concentrated to give 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3.53 g, 89%). 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J=2.5, 1H), 7.52 (dt, J=28.5, 14.2, 1H), 6.97 (d, J=8.7, 1H), 4.95 (dd, J=7.6, 6.8, 1H), 4.53-4.36 (m, 1H), 4.17 (ddd, J=12.8, 9.9, 4.4, 1H), 3.04-2.84 (m, 1H), 2.52 (ddt, J=14.7, 7.8, 4.5, 1H)