Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:18][NH:19][C:20]([NH2:22])=[S:21]>O1CCCC1>[CH3:18][NH:19][C:20]1[S:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[N:22]=1
Reactant: CNC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NC)nc1-c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (0.65 g, 2.2 mmol) in 20 mL of tetrahydrofuran was added N-methylthiourea (0.20 g, 2.2 mmol). The resulting mixture was stirred at 65° C. for 16 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with hexanes/ethyl ether left the title compound as an off-white solid (0.46 g, 73%). MS (ESI) 288.3 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH2:24])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:33]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>ClCCl>[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH:24][S:43]([C:40]1[CH:41]=[CH:42][C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:38][CH:39]=1)(=[O:45])=[O:44])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
A solution of 0.395 g (1 mmol) of (2S)-2-amino-3-((5-(2-methoxycarbonylethyl)-thiophene-2-carbonyl)-amino)-propionic acid tert-butyl ester hydrochloride (example 15, step a) and triethylamine (0.15 ml, 1.1 mmol) in dichloromethane (10 ml) was cooled to 0° C. in an ice bath and a solution of 0.255 g (1.1 mmol) of 4-tert-butylphenylsulfonyl chloride in dichloromethane (5 ml) was added. Then the reaction mixture was stirred at room temperature overnight. After removal of the solvent in vacuo the residue was absorbed onto silica gel and cromatographed with ethyl acetate/cyclohexane (1/1) to yield 0.285 g (52%) of the title compound as a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[C:5](=[CH:10][C:11]([N:14]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[C:5](=[CH:10][C:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N(Cc2ccccc2)c2ccccc2[N+](=O)[O-])cc1C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N(Cc2ccccc2)c2ccccc2N)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A clear solution of stannous chloride dihydrate (0.84 g, 3.72 mmol) in DMF (4ml) was added to a solution of 4-[benzyl-(2-nitrophenyl)amino]phthalic acid dimethyl ester (195 mg, 0.47 mmol) in DMF (4ml) and stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate (2×25 ml). The collected organic phases was washed with water (3×25 ml), dried over magnesium sulphate, and evaporated to dryness in vacuo to give 4-[(2-aminophenyl)benzylamino]phthalic acid dimethyl ester as a slightly coloured oil (yield: 180 mg (100%)).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][N:14]=2)[O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.CCN(C(C)C)C(C)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH:3]1[CH2:2][NH:1][C:30](=[O:32])[N:12]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:19]=[C:11]12
Reactant: NCC(OC1CCCCO1)c1cc2cccnc2[nH]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NCC(OC2CCCCO2)c2cc3cccnc3n21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 210.9 %

Procedure:
A solution of 9a (7.4 g, 28 mmol) and DIPEA (5 ml, 28 mmol) in CH2Cl2 (300 ml) was slowly added to a solution of triphosgene (2.82 g, 10 mmol) in CH2Cl2 (740 ml) and the mixture was stirred at room temperature for 30 min. The organic mixture was washed with saturated aq. NH4Cl and with water. The organic solution was dried and evaporated to give a diastereomeric mixture (1:1) of 10a (6.06 g, 76%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])(OCC)=O>O>[CH:29]1[CH:28]=[C:25]2[C:26]([N:1]([C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([NH2:6])=[O:7])[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=1)=[O:27]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a stirred solution of L-glutamine (43.8 g, 300 mmoL) and sodium carbonate (33.4 g, 315 mmoL) in 750 mL of water is rapidly added N-carbethoxyphthalimide [65.8 (97% pure, 67.8 g), 300 mmoL] as a solid. After 1 hour, the reaction mixture is filtered to remove unreacted N-carbethoxyphthalimide. The pH of the stirred filtrate is adjusted to 3-4 with 4N hydrochloric acid. The mixture is then seeded with N-phthaloyl-L-glutamine and the pH adjusted to 1-2 with 4 N hydrochloric acid. The resulting slurry is stirred for 1 hour. The slurry is filtered and the solid washed with copious amounts of water. The solid is air-dried and then dried in vacuo (60° C., <1 mm) overnight to afford 49.07 g (59%) of N-phthaloyl-L-glutamine, which can be alternatively named as 2-phthalimidoglutaramic acid, as a white powder.
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1.[CH2:32](N(CC)CC)C.CI>C(Cl)Cl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:26][CH2:27][N:28]([CH3:32])[CH2:29][CH2:30]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: CCN(CC)CC
Reactant: FC1(F)Oc2ccc(-c3c[nH]c4ncc(-c5cnn(C6CCNCC6)c5)cc34)cc2O1
Solvent: ClCCl
Solvent: CI
Product: CN1CCC(n2cc(-c3cnc4[nH]cc(-c5ccc6c(c5)OC(F)(F)O6)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine (17.9 mg, 0.236 mmol). Methyl iodide (18.3 mg, 0.130 mmol) was added to the reaction and stirred for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 341.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11](Cl)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: C1COCCN1
Product: O=c1c2[nH]c(N3CCOCC3)nc2n(CC2CC2)c(=O)n1CC1CC1

Procedure:
1,3-Di-cyclopropylmethyl-8-morpholino xanthine was prepared from 1,3-di-cyclopropylmethyl-8-chloroxanthine (0.3 g, 0.001 mol) and morpholine (0.2 g, 0.0022 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. >250° C., yield 0.09 g (26%).
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:18](OCC)(=O)[CH2:19][OH:20].Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:18]([CH2:19][OH:20])=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)CO
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(CO)nc(=O)c1-2
Yield: 23.4 %

Procedure:
Sodium (0.68 g) was dissolved in ethanol and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.0 g, 13.5 mmol), followed by ethyl glycolate (2.8 g, 27 mmol) were added. The reaction mixture was refluxed overnight, the ethanol was stripped and water, followed by 2N HCl were added to the residue. A precipitate formed which was collected by filtration, washed with saturated NaHCO3, and then water. The product was recrystallized from ethyl acetate, then ether to afford 0.83 g of 1-cyclopentyl-3-ethyl-6-(hydroxymethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 183-184° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.N1C=CC=CC=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>CCOCC>[N+:8]([C:6]1[CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])[CH:7]=1)([O-:10])=[O:9]
Reactant: CCOc1cc([N+](=O)[O-])cc(N)n1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOc1cc([N+](=O)[O-])cc(NC(=O)CCl)n1
Reaction time: 0.33 h

Procedure:
A solution of 2-amino-4-nitro-6-ethoxypyridine (29.4 grams) in absolute ether (150 ml), and pyridine (25 grams) are charged into a glass reaction vessel equipped with stirrer, thermometer and addition funnel. The mixture is cooled to a temperature of about 0° C and chloroacetyl chloride (11.3 grams) dissolved in ether (50 ml) is then slowly added thereto with stirring over a period of about 20 minutes. Stirring and cooling are continued for an additional period of about 30 minutes. The resulting precipitate is then recovered from the reaction medium by filtration, is washed first with aqueous sodium carbonate and then with water, and is dried to yield the desired product N-(4-nitro-6-ethoxy-2-pyridyl)-α-chloroacetamide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.CO.[CH3:11][NH2:12]>O>[CH3:11][NH:12][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN
Solvent: CO
Solvent: O
Product: CNc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.7 %

Procedure:
3,6-Dichloropyridazine (107, 500 mg, 3.36 mmol) was slowly added to a 2.0 M methylamine methanol solution (NH2Me in MeOH, 5 mL, 10 mmol) and stirred at room temperature for 24 hours. Water was added to the reaction mixture, and organic compounds were extracted with ethyl acetate. The recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 3-(N-monomethylamino)-6-chloropyridazine (108e, 505 mg, 88%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36].[NH2:37][CH2:38][CH2:39][N:40]([CH3:48])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:37][CH2:38][CH2:39][N:40]([CH3:48])[C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[CH:28]=[CH:29][C:30]=3[CH3:31])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCN(C)C(=O)OC(C)(C)C)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (1.59 g, 3.1 mmol), was dissolved in CH2Cl2 (140 mL) and stirred under argon at room temperature. 1,1-dimethylethyl (2-aminoethyl)methylcarbamate (0.806 g, 4.65 mmol), and TEA (0.87 mL, 6.2 mmol) were combined in CH2Cl2 (10 mL) and added to the solution of the sulfone. The resulting reaction mixture was stirred under argon overnight. The solvents were pumped off in vacuo. The residue was flash chromatographed on silica gel (150 g) eluted with 0-40% EtOAc/CH2Cl2 to give the title compound as a white amorphous solid. mp 115-118° C. LC-MS m/z 607 (M+H)+, 2.27 min (ret time).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([S:56]([NH:59][CH3:60])(=[O:58])=[O:57])[CH:44]=[CH:45][C:46]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([S:56]([NH:59][CH3:60])(=[O:58])=[O:57])[CH:44]=[CH:45][C:46]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: CNS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c(OC)c1
Yield: 80.4 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with 3-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (72 mg, 0.22 mmol), sodium carbonate (23 mg, 0.22 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (21 mg, 0.03 mmol) in 1,2-dimethoxyethane (1.60 ml) and water (0.40 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 46 mg (73% yield) of the title compound.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+](C)C.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([CH:18]=[CH2:19])[CH:12]=1>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N+:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH3:10])=[CH:12][C:13]=1[CH:18]=[CH2:19]
Reactant: C[O+](C)C
Reactant: C=Cc1cc(C)cc(C)n1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C=Cc1cc(C)cc(C)[n+]1C

Procedure:
Trimethyloxonium tetrafluoroborate (0.50 g; 3.76×10-3 mol) is added in one portion to a solution of 4,6-dimethyl-2-vinylpyridine (0.61 g; 4.13×10-3 mol) in 4.0 ml of methylene chloride under an inert atmosphere. The suspension is left to react for 2 h at 25° C. The suspension is filtered and the product is dried under vacuum. Yield=0.162 g (18%), white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([Br:23])[CH:15]=1)=[O:12])([O-:3])=[O:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([N:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([Br:23])[CH:15]=1)[C:11](=[O:12])[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:27]
Reactant: CCOc1ccc(NC(=O)Nc2ccccc2[N+](=O)[O-])cc1Br
Reactant: O=C(Cl)CCl
Product: CCOc1ccc(N(C(=O)CCl)C(=O)Nc2ccccc2[N+](=O)[O-])cc1Br

Procedure:
A solution containing N-(2-Nitrophenyl)-N'-(3-bromo-4-ethoxyphenyl)-urea (5.76 g) and chloroacetyl chloride (413 mL) was refluxed under nitrogen for 30 min. After the excess chloroacetyl chloride was removed in vacuo. diethyl ether (50 mL) was added and the resulting solid was filtered and dried to yield N'-(2-chloroacetyl)-N-(2-nitrophenyl)-N'-(3-bromo-4-ethoxyphenyl)-urea as a white solid.
Reaction SMILES: [F:1][C:2]1[C:8]([Cl:9])=[C:7]([O:10][CH:11]([CH3:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:6]([Cl:20])=[CH:5][C:3]=1[NH2:4].[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>ClCCCl>[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([NH:26][C:27]([NH:4][C:3]1[CH:5]=[C:6]([Cl:20])[C:7]([O:10][CH:11]([CH3:19])[C:12]([F:18])([F:17])[C:13]([F:15])([F:16])[F:14])=[C:8]([Cl:9])[C:2]=1[F:1])=[O:28])=[O:25]
Reactant: CC(Oc1c(Cl)cc(N)c(F)c1Cl)C(F)(F)C(F)(F)F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: ClCCCl
Product: CC(Oc1c(Cl)cc(NC(=O)NC(=O)c2c(F)cccc2F)c(F)c1Cl)C(F)(F)C(F)(F)F
Reaction time: 8 h
Yield: 39.1 %

Procedure:
200 mg of 2-Fluoro-3,5-dichloro-4-(1-methyl-2,2,3,3,3-pentafluoropropoxy)aniline was stirred in 15 mL 1,2-dichloroethane as 118 mg 2,6-difluorobenzoyl isocyanate in 5 mL 1,2-dichloroethane was added. The mixture was heated under reflux for 30 minutes before lowering heat and stirring overnight. The mixture was then concentrated to half volume and chilled to give 120 mg of 1-(2,6-Difluorobenzoyl)-3-[2-fluoro-3,5-dichloro-4-(1-methyl-2,2,3,3,3-pentafluoropropoxy)phenyl]urea as a white solid. 1H NMR: 10.60 (s, 1H), 9.46 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.54 (m, 1H), 7.08 (t, J=8.7 Hz, 2H), 5.11 (m, 1H), 1.43 (d, J=6.7 Hz, 3H). MS: 524 m/z. IR: 1699(s), 1469(s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:20]=1>O1CCCC1.C(O)C.[Pt](=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:20]=1
Reactant: COc1ccc(C=Cc2cc3cc(Br)ccc3o2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CCc2cc3cc(Br)ccc3o2)cc1
Reaction time: 4 h
Yield: 75.4 %

Procedure:
128 g of 5-bromo-2-[2-(4-methoxyphenyl)vinyl]benzofuran as a mixture of two stereoisomers was dissolved in a solvent mixture of 1.3 l of tetrahydrofuran and 0.7 l of ethanol. The resulting solution was mixed with 3.0 g of platinum dioxide and subjected to 4 hours of catalytic hydrogenation undernormal pressure. Thereafter, the catalyst was removed by filtration, the resulting filtrate was concentrated, and crystals thus precipitated were collected by filtration and washed with ethanol. In this way, 97.08 g of 5-bromo-2-[2-(4-methoxyphenyl)ethyl]benzofuran was obtained.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH:25]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([S:34][CH:31]5[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]5)[CH:24]=[CH:23][C:5]=43)[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CC(C)N1CCC(S)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(SC4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 120 °C
Yield: 70.5 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (150 mg, 0.386 mmol), 1-isopropylpiperidine-4-thiol (92 mg, 0.579 mmol), Pd2(dba)3 (18 mg, 5 mol %), XantPhos (23 mg, 10 mol %) and DIPEA (0.27 mL, 1.54 mmol) in dioxane (4 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. After cooling to RT, the crude mixture was diluted with DCM (75 mL) and purified by column chromatography (Si-PCC, gradient 0-6% 2N NH3/MeOH in DCM followed by C18, gradient 20-50% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless solid (127 mg, 70%). LCMS: RT 3.00 min [M+H]+ 467.1
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:14][C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][C:5]1=2>[Pd].C1C2C(CCCC2)CCC1.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2[C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:14][C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][C:5]1=2
Reactant: OCCn1c2c(c3c(N4CCCC4)nc(N4CCCC4)nc31)CCCC2
Agent: [Pd]
Solvent: C1CCC2CCCCC2C1
Solvent: ClCCl
Product: OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21

Procedure:
A mixture of 9-(2-hydroxyethyl)-2,4-di-1-pyrrolidinyl-5,6,7,8-tetrahydro-9H-pyrimido[4,5-b]indole (VII, EXAMPLE2, 5.14 g) and palladium on carbon (10%, 1.4 g) in decalin (250 mL) is heated at reflux for 3 hr. The mixture is cooled to 20°-25°, diluted with methylene chloride (250 mL) and filtered through diatomaceous earth. Removal of the solvent from the filtrate, followed by chromatography (silica gel, 1% methanol/chloroform) of the resulting residue gives the title compound, mp=110°-111; MS (m/z) 351, 323, 307, 296 and 279; NMR (CDCl3) 7.89, 7.23, 7.13, 6.97, 4.38, 4.05, 3.92, 3.62 and 2.0-1.9 δ.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[CH2:28]([O:27][C:25]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4s3)CC2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Cc2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
A solution of 500 mg of 1-benzyl-4-((benzothiazol-2-yl)methyl)piperidine (from EXAMPLE 163, Step D) in 10 mL of THF was added 185 mg of ethyl chloroformate at rt. The reaction was stirred at rt for 5 h. The reaction mixture was partitioned between H2O and EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic phases were washed with sat'd NaCl and dried over MgSO4. Concentration afforded 320 mg of the title compound as a oil.