Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([Sn](CCCC)(CCCC)CCCC)=[CH2:5])[CH3:2].[NH2:19][C:20]1[N:41]=[C:40](Cl)[CH:39]=[CH:38][C:21]=1[C:22]([NH:24][CH2:25][C:26]1[S:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)=[O:23].C1(C)C(C)=CC=CC=1.O>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(OCC)(=O)C>[NH2:19][C:20]1[N:41]=[C:40]([C:4]([O:3][CH2:1][CH3:2])=[CH2:5])[CH:39]=[CH:38][C:21]=1[C:22]([NH:24][CH2:25][C:26]1[S:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)=[O:23]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: C=C(OCC)c1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 130 °C
Reaction time: 2.5 h
Yield: 82.6 %

Procedure:
1-Ethoxyvinyl(tri-n-butyl)tin (0.47 mL, 1.4 mmol) was added to a mixture of 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (170 mg, 0.46 mmol) described in Preparation Example A+-11, tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.046 mmol) and xylene (5 mL), and the solution was stirred for 2.5 hours at 130° C. After cooling, water and ethyl acetate were added to the reaction solution for extraction, and the solution was washed with brine. The solvent was evaporated in vacuo, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1), and the title compound (150 mg, 0.38 mmol, 82%) was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:26][CH3:30])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: C#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(OC)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (2.6 g, 7.0 mmol) is dissolved in N,N-dimethylformamide (30 ml). Sodium hydride (0.18 g, 7.5 mmol) is added in portions at +5° C. The mixture is stirred for 30 minutes at room temperature. Subsequently iodomethane (1.1 g, 7.5 mmol) is added dropwise and the resulting mixture is stirred for 3 more hours at room temperature. The reaction mixture is poured on ice/water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic layer is washed with brine (200 ml) and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by chromatography (ethyl acetate/hexane) to yield 2-(4-chloro-phenyl)-2-methoxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:31][Si:32]([C:35]#[C:36][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)([CH3:34])[CH3:33]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 90 °C

Procedure:
21.5 g (0.1 mol) of methyl 4-bromobenzoate, 300 ml of triethylamine and a mixture of 200 mg of palladium acetate and of 400 mg of triphenylphosphine were introduced into a three-necked flask under a stream of nitrogen. 20 g (0.204 mol) of trimethylsilylacetylene were then added, the mixture was heated progressively to 90° C. over 1 hour and maintained at this temperature for 5 hours. The reaction mixture was cooled, the salt filtered and evaporated. The residue was taken up with 200 ml of hydrochloric acid (5%) and 400 ml of ethyl ether. The ether phase was separated by settling, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column diluted with dichloromethane. After the evaporation of the solvents, 23 g (100%) of the expected compound were recovered in the form of a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8].C(O)(=O)C(O)=O.[CH3:18][N:19]([CH2:21][C:22]1[O:26][C:25]([CH2:27][SH:28])=[CH:24][CH:23]=1)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[CH3:20][N:19]([CH2:21][C:22]1[O:26][C:25]([CH2:27][S:28][CH2:2][CH2:3][NH:4][C:5]([NH:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8])=[CH:24][CH:23]=1)[CH3:18]
Reactant: CNC(=C[N+](=O)[O-])NCCCl
Reactant: CN(C)Cc1ccc(CS)o1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 120 h
Yield: 63.9 %

Procedure:
A mixture of N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (0.9 g), 5-[(dimethylamino)methyl]-2-furanmethanethiol oxalate (1:1) (1.3 g) and potassium carbonate (2.7 g) in water (10 ml) and tetrahydrofuran (10 ml) was stirred under nitrogen at room temperature for 5 days. The suspension was evaporated in vacuo, the residue mixed with water (40 ml) and the suspension extracted with ether (2×30 ml). The aqueous fraction was evaporated in vacuo and the residue evaporated with ethanol (2×10 ml). Tetrahydrofuran (20 ml), MgSO4 and decolourising charcoal were added and after 1 hour the mixture was filtered. Evaporation of the filtrate gave an oil (1 g) which was chromatographed (silica/methanol: 0.88 ammonia, 79:1). The appropriate eluate was evaporated and the oily residue (0.66 g) extracted with hot isopropyl acetate. The solid which separated was filtered to give the title compound (0.4 g), m.p. 65°-68°, which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent No. 1,565,966.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:32])[C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:8]=[C:7]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[N:6]=1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:32][N:4]([C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[N:6]=1)[CH2:3][CH2:2][OH:1]
Reactant: Cc1ccnc(Nc2cc(C3CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)CCO)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccnc(Nc2cc(C3CCNCC3)cc(N(C)CCO)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
To a solution of tert-butyl 4-(2-((2-hydroxyethyl)(methyl)amino)-6-(4-methylpyridin-2-ylamino)pyridin-4-yl)piperidine-1-carboxylate (100 mg, 0.22 mmol) in DCM (1.0 mL) was added hydrogen chloride (4 mol/L) in 1,4-dioxane (3.0 mL, 12 mmol). The resultant was stirred at room temperature for 3 h. It was purified by HPLC to give 37 mg (48%) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.95 (s, 1H), 6.64 (d, J=5.1 Hz, 1H), 6.42 (s, 1H), 5.90 (s, 1H), 4.64 (s, 1H), 3.64-3.53 (m, 4H), 3.05-2.95 (m, 5H), 2.58-2.52 (m, 1H), 2.50-2.31 (m, 3H), 2.25 (s, 3H), 1.69-1.58 (m, 2H), 1.55-1.40 (m, 2H). LC-MS: m/z=342 (M+H+).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH2:15][CH3:16])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[OH2:17].ClCCl>CCC(O)CC.CN(C=O)C>[CH2:15]([C:5]1[C:4]([O:17][CH:5]([CH2:15][CH3:16])[CH2:6][CH3:7])=[N:9][N:8]2[C:10]([NH2:13])=[N:11][N:12]=[C:7]2[C:6]=1[CH3:14])[CH3:16]
Reactant: CCc1c(Cl)nn2c(N)nnc2c1C
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(O)CC
Solvent: CN(C)C=O
Product: CCc1c(OC(CC)CC)nn2c(N)nnc2c1C
Reaction time: 8 h

Procedure:
3-Pentanol (2.5 ml) was initially charged at RT with stirring. Thereafter, sodium hydride (91 mg) was added while cooling with ice. After stirring at 55° C. for 2.5 h, 6-chloro-7-ethyl-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.007; 120 mg), dissolved in 3-pentanol (2 ml) and DMF (4 ml), was added dropwise. After stirring for 1 h, the mixture was left to stand at RT overnight, and the reaction mixture was admixed with water and dichloromethane and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 126 mg of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.Cl>O1CCCC1.CCCCCC>[CH3:11][N:12]1[CH2:17][CH2:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])([OH:18])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCC(O)(c2ccccc2[N+](=O)[O-])CC1
Temperature: -100 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of 19.3 g of 2-bromonitrobenzene in 480 ml of anhydrous tetrahydrofuran cooled to -100° C., 79 ml of 1,6M solution of n-Buli in hexane are dropped under N2. After two hours 10.9 g of 1-methyl-4-piperidone are added and the resulting mixture is stirred eight hours at -100° C. Then 1N hydrochloric acid is added at 0° C. to acidify to pH 2 and the solution is extracted with hexane. The aqueous phase is brought to pH 10 and extracted with ethyl ether. Evaporation of the extracts gives 8.95 g of 1-methyl-4(2-nitrophenyl)-4-hydroxypiperidine, m.p. 166°-167°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[N:14]=[C:15]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=O)[NH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C.C(OCC)(=O)C.CO>O1CCCC1>[C:7]1([C:13]2[N:14]=[C:15]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[NH:16][C:17]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCCCNC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCNCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
Part B. To a solution of lithium aluminum hydride (0.96 g, 0.025 mol) in dry tetrahydrofuran (30 mL) was added, dropwise, a solution of 8-(4,5-diphenyl-1H-imidazole-2-ylthio)-N-heptyloctanamide (2.82 g, 0.0057 mol) in tetrahydrofuran (15 mL) and the reaction mixture was stirred at reflux for 18 hours. The reaction mixture was cooled to 0°, quenched by the slow and careful sequential addition of water (0.96 mL), 15% sodium hydroxide (2.88 mL), and water (2.88 mL), and then stirred at 0° for 30 minutes. The solution was then dried over magnesium sulfate and concentrated, and the residue was chromatographed with 1:1 hexane:ethyl acetate and then with a gradient of 1:0 to 3:1 to 1:1 ethyl acetate-methanol to give 8-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptyl-1-octanamine (1.07 g, 0.0022 mol) as a white solid, mp 87°-89°. 1H NMR (CDCl3) δ7.6- 7.2(m,11H), 3.1(t,2H,J=7Hz), 2.7-2.5(m,2H), 1.8-1.1(m,25H), 0.9(t,3H,J=8Hz).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:19]([NH:21][NH:22][S:23]([NH:26][CH2:27][C:28]([O:30]C)=[O:29])(=[O:25])=[O:24])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl.O1CCC[CH2:41]1>CO.O>[CH3:41][CH:27]([NH:26][S:23]([NH:22][NH:21][C:19](=[O:20])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:32][CH:33]([CH3:34])[CH3:35])(=[O:24])=[O:25])[C:28]([OH:30])=[O:29]
Reactant: COC(=O)CNS(=O)(=O)NNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NNS(=O)(=O)NC(C)C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 0.431 g of methyl(E)-2-[[2-[2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]hydrazino]sulphonamido]acetate in 10 ml of tetrahydrofuran and 5 ml of methanol was treated with 0.040 g of lithium hydroxide monohydrate and the mixture was left to stir overnight. A further 0.020 g of lithium hydroxide monohydrate was added and stirring continued for 4 hours. The mixture was then diluted with water, acidified using 2M aqueous hydrogen chloride, and extracted with ethyl acetate. The ethyl acetate fraction was dried over anhydrous magnesium sulphate and evaporated to give 0.462 g of methyl(E)-2-[[2-[2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]hydrazino]sulphonamido]acetic acid as an oil.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.CCO.O>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.O>[Cl:17][C:18]1[CH:23]=[C:22]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1cccc(-c2ccc3[nH]ccc3c2)c1
Yield: 100.5 %

Procedure:
A stirred slurry of 4.23 g (40 mmol) Na2CO3, 1.84 g (9.4 mmol) 5-bromoindole, 1.88 g (10 mmol) 3-chlorophenylboronic acid, and 0.29 g (0.25 mmol) Pd(PPh3)4 in 50 mL 1:1 EtOH-water was heated to reflux for 2.5 hours. The reaction mixture was allowed to cool and was then poured into 400 mL water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, and concentrated to afford 2.15 g crude 5-(3-chlorophenyl)indole as a tan solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]([C:19](O)=[O:20])=[C:9]1[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29][NH2:30].C(Cl)CCl.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]([C:19]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([F:34])=[C:26]([F:25])[CH:27]=2)=[O:20])=[C:9]1[CH:22]([CH3:23])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: COc1cc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Compound 8, 6.0 mg, 0.019 mmol) and 3,4-difluorobenzylamine (7.0 I, 0.057 mmol) in CH2Cl2 (1.0 ml) was added EDC (5.5 mg, 0.029 mmol), DMAP (3.5 mg, 0.029 mmol), and Et3N (25 l). The mixture was stirred at room temperature for 16 h and was directly purified by preparative thin layer chromatography (PTLC) on silica gel (50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:21][C@:20]3([CH3:34])[C@@H:22]([CH3:33])[CH2:23][CH2:24][C@H:25]4[C:26]([CH3:32])([CH3:31])[C@@H:27]([OH:30])[CH2:28][CH2:29][C@@:19]34[O:18][C:11]=2[C:12]2[CH2:13][NH:14][CH2:15][C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]2[CH2:21][C@:20]3([CH3:34])[C@@H:22]([CH3:33])[CH2:23][CH2:24][C@H:25]4[C:26]([CH3:32])([CH3:31])[C@@H:27]([OH:30])[CH2:28][CH2:29][C@@:19]34[O:18][C:11]=2[C:12]2[CH2:13][N:14]([C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:15][C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CNC4
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CN(C(=O)CCC(=O)O)C4
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
To a solution of Compound (33a) (38 mg, 0.08 mmol) in dry pyridine (0.4 ml) was added 16 mg (0.16 mmol) of succinic anhydride, and the mixture stirred for 1 hour at room temperature. Ice-water was added to the reaction, followed by extraction with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (silica gel 2.0 g; chloroform:methanol:water=9:1:0.1) to give 46 mg (100%) of Compound (33c).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17](=[O:19])[CH3:18])(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][C:31]([NH2:34])([CH3:33])[CH3:32].N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1>>[ClH:20].[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[CH:29][CH:28]=2)[C:24]([CH2:30][C:31]([NH:34][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][C:17](=[O:19])[CH3:18])([CH3:32])[CH3:33])=[CH:25]1
Reactant: CC(=O)COc1ccccc1OCCOS(C)(=O)=O
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Product: CC(=O)COc1ccccc1OCCNC(C)(C)Cc1c[nH]c2ccccc12
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(2-oxopropyloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl]{2-[2-(2- oxopropyloxy)phenoxy]ethyl}amine hydrochloride.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:30]4[CH2:31][CH2:32][CH:26]3[CH2:27][N:28]([CH:33]3[CH2:36][O:35][CH2:34]3)[CH2:29]4)=[CH:21][N:20]=2)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[C@@H:30]4[CH2:31][CH2:32][C@H:26]3[CH2:27][N:28]([CH:33]3[CH2:36][O:35][CH2:34]3)[CH2:29]4)=[CH:21][N:20]=2)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C5CCC4CN(C4COC4)C5)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3[C@@H]4CC[C@H]3CN(C3COC3)C4)cn2)c1=O
Temperature: 35 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
A mixture of 152f (180 mg, 0.26 mmol) and lithium hydroxide (215 mg, 5.1 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 35° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water and ethyl acetate. The water phase was separated and extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 152 (12 mg, 71%) as a yellow solid. MS-ESI: [M+H]+ 663.3. 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=2.5 Hz, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.32 (s, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.33 (d, J=5.0 Hz, 1H), 7.25-7.23 (m, 1H), 7.20 (d, J=9.0 Hz, 1H), 6.57 (s, 1H), 4.96-4.94 (m, 1H), 4.48-4.43 (m, 3H), 4.39-4.37 (m, 3H), 4.25-4.19 (m, 5H), 3.85 (d, J=11.5 Hz, 1H), 3.59 (s, 3H), 2.66-2.54 (m, 4H), 2.40-2.36 (m, 3H), 2.17 (d, J=10.5 Hz, 2H), 1.94-1.65 (m, 8H).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=O.[NH:12]([CH2:14]C(O)=O)[CH3:13]>CS(C)=O.C(OCC)(=O)C>[CH3:13][N:12]1[C:4](=[O:10])[C:5]2[S:9][CH:8]=[CH:7][C:6]=2[NH:1][C:2](=[O:3])[CH2:14]1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN1CC(=O)Nc2ccsc2C1=O
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 30.0 g (177 mmol) of 2H-thieno[3,2-d][1,3]-oxazine-2,4(1H)-dione and 17.3 g (195 mmol) of sarcosine in 100 ml of dimethyl sulphoxide is stirred at 110° C. for 1.5 hours. The dark brown coloured solution is poured into ca 600 ml of ice/water. The separated oil is taken up in ca 200 ml of ethyl acetate and the aqueous phase is evaporated in vacuo until crystallisation begins. The mixture is cooled in an ice-bath for ca 3 hours and the separated material is filtered off under suction and washed with a small amount of water. After drying on a rotary evaporator, there is obtained 3,4-dihydro-4-methyl-2H-thieno[3,2-e][1,4]diazepine-2,5(1H)-dione of melting point 270°-272° C.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)CC.Cl[C:35]1[N:36]=[CH:37][C:38]([C:41]#[N:42])=[N:39][CH:40]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH:29][C:35]5[N:36]=[CH:37][C:38]([C:41]#[N:42])=[N:39][CH:40]=5)[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: N#Cc1cnc(Cl)cn1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](Nc5cnc(C#N)cn5)C4)n23)cc1
Temperature: 150 °C
Yield: 81.2 %

Procedure:
To a microwave vessel was added (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.500 g, 1.06 mmol), n-propanol (10 mL), 5-chloropyrazine-2-carbonitrile (0.223 g, 1.60 mmol) and DIEA (0.837 mL, 4.79 mmol). The resulting mixture was heated in a microwave at about 150° C. for about 30 min. DCM (100 mL) was added and a solution was formed. The organic solution was washed with water and brine (50 mL each), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a brown solid. The residue was taken up in DCM (30 mL) and adsorbed onto silica gel (5 g). The material was purified by silica gel chromatography (80 g cartridge) eluting with neat EtOAc to give 5-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl-amino)pyrazine-2-carbonitrile (0.43 g, 80%) as a light yellow solid: LC/MS (Table 2, Method d) Rt=1.40 min; MS m/z: 500 (M+H)+.