Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3ccccn3)ccc21
Product: CC1c2ccc(-c3ccccn3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22]>COCCOC>[O:23]=[C:21]([CH3:22])[CH2:20][N:6]([S:7]([CH3:10])(=[O:9])=[O:8])[C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CS(=O)(=O)Nc1ccc(Cl)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(=O)CN(c1ccc(Cl)cc1)S(C)(=O)=O

Procedure:
A mixture of 4'-chloro-methanesulphonanilide (10.0 g), anhydrous potassium carbonate (4.0 g), chloroacetone (4.8 ml), and 1,2-dimethoxyethane was stirred and boiled under reflux for 24 hours, and then filtered, and the filtrate was evaporated. The oily residue was dissolved in ether, and the solution was washed with water, dried (MgSO4) and evaporated. The residue gave almost colourless crystals from acetone/40°-60° petrol. Melting point 108°. Yield 4.1 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][O:25][C:21](=[O:24])[CH:22]=[CH:23][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:3]=1
Reactant: Brc1cccc(Sc2cccc(-c3ccccc3)n2)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cccc(Sc2cccc(-c3ccccc3)n2)c1
Reaction time: 0.33 h

Procedure:
Crude aryl bromide (14) (100 mg, 0.18 mmol), methyl acrylate (18 mg, 0.21 mmol), triethylamine (71 mg, 0.70 mmol), tri(o-toly)phosphine (5 mg, 0.016 mmol) and palladium(II) acetate (12 mg, 0.054 mmol) in acetonitrile (2 mL) was heated in a CEM Discover microwave for 45 minutes at 90° C. More tri(o-toly)phosphine (3 mg) and palladium(II) acetate (3 mg) were added and the reaction mixture retreated in the microwave for 20 minutes; palladium(II) acetate (2 mg) was then added and the process repeated for a further 25 minutes. The solvent was removed under a stream of nitrogen gas, water was added, and the organics extracted with EtOAc, washed with water, dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was partially purified by column chromatography. Yield: 51 mg, 60%; LC-MS tr 1.82 min; HPLC Purity: 70%; MS (ES+) m/z 348 (M+H)
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:10][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29].C(O)(C)C>ClCCl>[Br:1][C:2]1[C:3]([C:9]2[S:10][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)=[N:4][C:5]([NH:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])=[N:6][CH:7]=1
Reactant: NCCN1CCNC1=O
Reactant: Clc1ncc(Br)c(-c2ccc(CN3CCCCC3)s2)n1
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C1NCCN1CCNc1ncc(Br)c(-c2ccc(CN3CCCCC3)s2)n1
Temperature: 170 °C
Yield: 61.8 %

Procedure:
5-Bromo-2-chloro-4-(5-(piperidin-1-ylmethyl)thiophen-2-yl)pyrimidine (0.3 g, 0.8 mmol), 1-(2-aminoethyl)imidazolidin-2-one (0.123 g, 0.96 mmol) and isopropyl alcohol were all placed in a microwave tube. The tube was capped and heated to 170° C. in a Personal Chemistry microwave for 10 min. The reaction then diluted with dichloromethane washed with water, saturated sodium bicarbonate, water and brine. The organic layer was dried with sodium sulfate and purified by flash chromatography using a gradient of 2 to 12% methanol in dichloromethane to give a light yellow solid (0.23 g). MS (M+H)+ 465/476.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:30][S:27]([O:26][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[CH:18][CH:17]=[C:16]2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:21][CH:22]=1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(OS(C)(=O)=O)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Oc1ccc2cccc(C(=O)N3CCNCC3)c2c1
Reaction time: 2 h

Procedure:
To a solution of the product from Step F (560 mg, 1.20 mmol) in dichloromethane (40 mL) at 0° C. was added trifluoroacetic acid (10 mL). The solution was stirred for 2 hours and then concentrated in vacuo to yield the titled compound.
Reaction SMILES: CO.[CH:3]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4]1.[BH4-].[Na+].CC(C)=O>C(Cl)(Cl)Cl>[CH:3]1([CH:6]([OH:7])[C:8]2[CH:9]=[CH:10][C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)[CH2:4][CH2:5]1
Reactant: CSc1ccc(C(=O)C2CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CSc1ccc(C(O)C2CC2)cc1
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To 200 ml of methanol solution containing 24 g of cyclopropyl (4-methylthiophenyl)ketone was added slowly 9.4 g of sodium borohydride under an ice-cooled condition, the reaction mixture was stirred for 2 hours. Then an adequate amount of acetone was added to the reaction mixture and concentrated under a reduced pressure. To the residue thus obtained was added chloroform, and the chloroform solution was washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by evaporation to yield 18 g of 1-(cyclopropyl, hydroxylmethyl)-4-methylthiobenzene as in the form of colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:8]=2[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=2)=[O:10])=[C:4]([CH3:35])[CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][C:8]=2[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:23][CH:24]=2)=[O:10])=[C:4]([CH3:35])[CH:3]=1
Reactant: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
tert-Butyl 4-[[2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]benzoate (43.8 mg, 0.09 mmol) was suspended in dichloromethane (1.45 mL) and TFA (1.45 mL) was added and the mixture stirred 0.5 h at room temperature. The reaction mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile and water (10-99%) and HCl as a modifier to yield 4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)benzoic acid (28) (24.71 mg, 67%). ESI-MS m/z calc. 433.09. found 434.3 (M+1)+; Retention time: 2.00 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 12.78 (s, 1H), 10.83 (s, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.94 (d, J=8.7 Hz, 2H), 7.80 (dd, J=15.4, 5.6 Hz, 3H), 7.18 (m, 3H), 6.83 (d, J=8.7 Hz, 1H), 2.14 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=2[F:22])[N:4]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:39]1(B(O)O)[CH2:41][CH2:40]1>CN(C=O)C.ClCCl.CO>[CH:39]1([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][C:9]=3[O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=3[F:22])[N:4]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:3]=2)[CH2:41][CH2:40]1
Reactant: OB(O)C1CC1
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccnc3c2c(C2CC2)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: 110 °C

Procedure:
500 mg (0.96 mmol) of N-[4-({3-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)-3-fluorophenyl]acetamide and 400 mg (2.89 mmol) of potassium carbonate are suspended in DMF (5 ml). The solution is degassed and vented with argon. 39 mg (0.05 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride/methylene dichloride complex and 207 mg (2.41 mmol) of cyclopropylboronic acid (Wallace, Debra J.; Chen, Cheng-yl; Tetrahedron Lett. 2002, 43(39), 6987-6990) are then added. The mixture is heated at 110° C. overnight. The reaction mixture is then dissolved in dichloromethane/methanol 10:1 and filtered through an Extrelut cartridge. The filtrate is concentrated under reduced pressure and the crude product is purified by preparative HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:32][CH2:33][OH:34]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:32][CH2:33][OH:34])[CH2:14][C@@H:13]1[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CNCC[C@H]1NC(=O)OCc1ccccc1
Reactant: OCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}piperidine-3-carboxylate (WO 2005/066176) (2.29 g, 7.83 mmol), N,N-diisopropylethylamine (2.05 mL, 11.75 mmol and 2-bromoethanol (0.722 mL, 10.18 mmol) in dry acetonitrile (17 mL) was heated in the microwave at 70° C. for 4.5 hours. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate (200 mL) and washed with saturated aqueous sodium hydrogencarbonate solution (100 mL). The aqueous phase was back extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (12:1) gave 2.0 g (76%), mp 73° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]=[C:13]1[O:17][C:15](=O)[CH2:14]1.C(OC(=O)C)(=O)C>CC(C)=O>[CH3:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:15]([CH2:14][C:13](=[O:17])[CH3:12])=[N:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: C=C1CC(=O)O1
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1nc2cccc(C)c2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of 2-amino-6-methylbenzoic acid (20 g, 0.132 mol) in acetone (100 mL), diketene (15.3 mL, 0.198 mol) was added dropwise at room temperature, and the mixture was stirred overnight at room temperature. The reaction solvent and excess diketene were concentrated and evaporated under reduced pressure, and tetrachloride (80 mL) were added to the residue, and subsequently acetic anhydride (27 g, 0.265 mol) was added thereto, and the mixture was heated under reflux for 3 hours. The reaction solvent and excess acetic anhydride were concentrated and evaporated under reduced pressure, and the resulting powder was collected, and washed with diethylether to give crude 5-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (13.75 g, 48% yield). A solution of the compound (12.99 g, 0.06 mol) and 2-hydrazinopyridine (7.18 g, 0.066 mol) in ethanol (100 mL) was heated under reflux for 1 hour. The reaction solution was allowed to cool to room temperature, the reaction solvent was concentrated and evaporated under reduced pressure. A solution of the residue in phosphorous oxychloride (45.8 g, 0.3 mol) was heated and stirred at 100° C. for 1 hour. The reaction solution was allowed to cool to room temperature, and the solvent was concentrated and evaporated under reduced pressure, and the residue was poured into iced water. A sodium hydroxide solution was added to the mixture to become basic, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) to give the title compound (4.4 g, 24% yield)
Reaction SMILES: [OH-].[CH3:2][Sn+:3]([CH3:5])[CH3:4].[N+:6]([C:9]1[O:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C1C=CC=CC=1>[N+:6]([C:9]1[O:13][C:12]([C:14]([O-:16])=[O:15])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH3:2][Sn+:3]([CH3:5])[CH3:4]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: c1ccccc1
Product: O=C([O-])c1ccc([N+](=O)[O-])o1
Temperature: 80 °C
Yield: 94 %

Procedure:
Trimethyltin 5-nitro-2-furoate (Compound E) was prepared by reacting trimethyltin hydroxide (9.20 g, 0.0509 mole) with 5-nitro-2-furoic acid (8.00 g, 0.0509 mole) in 75 ml benzene. The reaction mixture was refluxed for 19 hours at a temperature of 80° C. and a pressure of 1 atm. The resulting precipitate was collected on filter paper and dried to yield 15.30 g (94%) of crude trimethyltin 5-nitro-2-furoate, melting point 188.2°-195.5° C. The resulting compound was recrystallized three times from benzene to give Compound E, melting point 190°-192° C. The elemental analysis gave (in %) C:30.15, H:3.74, N:4.43, Sn:36.89, calculated for C8H11NO5Sn (in %): C:30.04, H:3.47, N:4.38, Sn:37.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:12][CH2:13][CH2:14]S(C)(=O)=O)[C:8]1=[O:27].[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:8]1=[O:27]
Reactant: COc1cc(CN2CCC(CCCS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Product: COc1cc(CN2CCC(CCCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6 using 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonylpropyl)-2-oxopyrrolidine (0.32 g, 0.63 mmol) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.30 g, 0.63 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/30% ethyl acetate/methanol to give the title compound: Rf=0.55 (silica gel, 2% triethylamine/methanol).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:32][O:33][C:34]([CH:36]1[CH:41](OS(C(F)(F)F)(=O)=O)[CH2:40][CH2:39][N:38]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:37]1)=[O:35].C([O-])(=O)C.[K+]>C(Cl)Cl.O>[CH3:32][O:33][C:34]([C:36]1[CH2:37][N:38]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:39][CH2:40][C:41]=1[C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)=[O:35]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1OCC2
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1=C(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 91.2 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (0.20 g, 0.49 mmol), 4-trifluoromethanesulphonyloxy-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.29 g, 0.75 mmol), potassium acetate (0.12 g, 1.22 mmol), Pd(dppf)2C12.DCM (0.04 g, 0.05 mmol), DME:IMS:water 7:2:1 (5 mL), were sealed in a microwave vial and heated by microwave irradiation at 120° C. for 10 min. The reaction mixture was cooled to RT, water and DCM were added, the organic layer separated, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% methanol in DCM) to give 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (239 mg, 91%). 1H NMR 300 MHz (CDCl3) δ: 8.49 (1H, d, J=8.30 Hz), 7.87 (1H, d, J=0.64 Hz), 7.64 (1H, s), 6.92 (1H, dd, J=8.31, 1.80 Hz), 6.84 (1H, d, J=1.77 Hz), 6.00 (1H, m), 4.49-4.47 (4H, m), 4.27 (2H, s), 3.62 (2H, t, J=5.69 Hz), 3.57 (2H, s), 2.50 (3H, s), 1.59 (6H, d, J=6.63 Hz), 1.51 (9H, s).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[CH2:5][C:4]1=[O:13])[CH3:2].[N+:14]([O-])([O-:16])=[O:15].[Na+]>FC(F)(F)C(O)=O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]=2[F:12])[CH2:5][C:4]1=[O:13])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCN1C(=O)Cc2cccc(F)c21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-Ethyl-7-fluoro-1,3-dihydro-indol-2-one (3.45 g, 19.3 mmol) is added portionwise to a mixture of sodium nitrate (1.64 g, 19.3 mmol) and trifluoroacetic acid (60 ml) and stirred at room temperature for 5 hours. The reaction is diluted with ice water and the resulting precipitate filtered, washed with water, and dried under vacuum to give the title compound as a brownish-yellow solid. HPLC r.t. 4.88 min; MS for C10H9FN2O3 m/z 223.0 (M-H)−.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[CH2:13][CH2:14][C:15](=[O:16])[C@@H:10]2[CH2:9]1)C1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>ClCCl>[O:16]=[C:15]1[C@@H:10]2[CH2:9][N:8]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:12][C@@H:11]2[CH2:13][CH2:14]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Solvent: ClCCl
Product: O=C1CC[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
A solution of (3aR,6aS)-2-benzyl-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrol-6-one (19.8 g, 92 mmol) in dichloromethane (770 mL) was treated with benzyl chloroformate (26.7 g, 22.3 mL, 156 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude material obtained was purified using silica gel column chromatography using 40 to 99% EtOAc in hexanes to obtain benzyl(3aR,6aS)-6-oxo-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (11.2 g, 43.19 mmol, 47%) as a light yellow oil. NMR (400 MHz, CDCl3) δ 7.41-7.23 (m, 5H), 5.11 (d, J=4.2 Hz, 2H), 3.82-3.52 (m, 3H), 3.29-3.14 (m, J=5.6 Hz, 1H), 3.13-2.93 (m, J=11.1, 6.8 Hz, 1H), 2.81-2.68 (m, J=8.6, 3.6 Hz, 1H), 2.37 (t, J=7.8 Hz, 2H), 2.26-2.10 (m, 1H), 1.86 (s, 1H). LC/MS m/z 260.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:3]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:3]1=[S:32]
Reactant: CCOC(=O)c1c(C)c2ccc(C(F)(F)F)cc2n(C)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)c2ccc(C(F)(F)F)cc2n(C)c1=S
Temperature: 120 °C
Yield: 80 %

Procedure:
A solution of 460 mg (1.5 mmol) ethyl 1,4-dimethyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylate in toluene (10 ml) was treated with 2.4 g (5.9 mmol) Lawesson's reagent at RT, followed by heating to 120° C. for 16 h. After cooling to RT the RS was quenched with a sat. aq. Na2CO3 solution (30 ml). The mixture was then extracted with EtOAc (3×30 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. CC (EtOAc/hexane 1:4) of the residue provided 400 mg (1.2 mmol, 82%) ethyl 1,4-dimethyl-2-thioxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:30]=[CH:29][C:13]([C:14]([NH:16][C@H:17]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[N:20]=2)[CH3:18])=[O:15])=[CH:12][C:11]=1[Cl:31])=[O:9].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:31][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][C:10]=1[C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[O:9])[C:14]([NH:16][C@H:17]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=2[N:20]=1)[CH3:18])=[O:15]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CS(=O)(=O)Cl
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CNS(C)(=O)=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 62 %

Procedure:
Prepared analogously to Example 125 from 4-((2R)-2-aminomethylpyrrolidin-1-ylcarbonyl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide, methanesulfonic acid chloride, and triethylamine in tetrahydrofuran. Yield: 62%; Rf value: 0.31 (silica gel; dichloromethane/ethanol=9:1); C23H25Cl2N5O4S (538.45); mass spectrum: (M+H)+=538/549/542 (chlorine isotope) and (M−H)−=536/538/540 (chlorine isotope).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16](OC)=[O:17])[CH:9]=[CH:8]1>O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][OH:17])[CH:9]=[CH:8]1
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2cc[nH]c12
Reaction time: 2 h

Procedure:
Solid lithium aluminum hydride (1.0 g) is added in portions over 1 hour to a stirred solution of methyl 7-indolecarboxylate (6.7 g) in tetrahydrofuran (100 ml). The mixture was stirred for a further 2 hours then excess lithium aluminum hydride was destroyed by addition of acetic acid, the mixture is diluted with aqueous sodium hydroxide and extracted with ethyl acetate. The extract is dried and evaporated and the residue is chromatographed on silica in ethyl acetate-hexane (1:9 to 1:2) to give the product.