Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([Sn](C)(C)C)=[C:9]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:10]=1)(=[O:4])=[O:3].I[C:34]1[S:35][CH:36]=[C:37]([CH3:39])[N:38]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.O.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].[Cu](I)I>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:34]2[S:35][CH:36]=[C:37]([CH3:39])[N:38]=2)=[C:9]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:10]=1)(=[O:4])=[O:3]
Reactant: Cc1csc(I)n1
Reactant: CS(=O)(=O)c1ccc([Sn](C)(C)C)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)n1
Temperature: 100 °C
Yield: 25.4 %

Procedure:
A mixture of (5-Methanesulfonyl-2-trimethylstannanyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (Example T, 100 mg, 0.17 mmol), 2-Iodo-4-methyl-thiazole ( CAS: 34203-25-3; 43 mg, 0.19 mmol), Bis(dibenzylideneacetone)palladium (8 mg, 0.01 mmol), Triphenylarsine (25 mg, 0.08 mmol) and Copper iodide (3 mg, 0.02 mmol) in N,N-Dimethylformamide (2 ml) was heated at 100° C. for 1 hour. The mixture was cooled to room temperature, diluted with water, and extracted three times with Ethyl acetate. The combined organic phases were dried with Na2SO4 ,filtered, and evaporated to dryness. The residue was chromatographed over SiO2 (methanol/dichoromethane 0% to 0.5%) to provide the title compound (22 mg, 25%) as a light yellow solid. MS (ISP): 510.5 MH+.
Reaction SMILES: [F:1][C:2]([F:5])(Br)Br.C(N(P(N(CC)CC)N(CC)CC)CC)C.[CH:22](/[CH:25]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:36][CH2:35][CH:34]([CH:37]=O)[CH2:33][CH2:32]2)[CH2:27][CH2:26]1)=[CH:23]\[CH3:24].Cl>C1COCC1>[F:1][C:2]([F:5])=[CH:37][CH:34]1[CH2:35][CH2:36][CH:31]([CH:28]2[CH2:29][CH2:30][CH:25](/[CH:22]=[CH:23]/[CH3:24])[CH2:26][CH2:27]2)[CH2:32][CH2:33]1
Reactant: C/C=C/C1CCC(C2CCC(C=O)CC2)CC1
Reactant: FC(F)(Br)Br
Agent: CCN(CC)P(N(CC)CC)N(CC)CC
Agent: Cl
Solvent: C1CCOC1
Product: C/C=C/C1CCC(C2CCC(C=C(F)F)CC2)CC1

Procedure:
Difluorodibromomethane (29.9 g) was dissolved in THF (100 ml), and then a tris(diethylamino)phosphine (63.4 g) THF (20 ml) solution and an (E)-4′-(prop-1-en-1-yl)-[1,1′-bi(cyclohexane)]-4-carbaldehyde (20.0 g) THF (20 ml) solution were sequentially added dropwise in an ice bath under a nitrogen atmosphere. After completion of the reaction, 1 N hydrochloric acid was added, and extraction was carried out with toluene. An organic layer was washed with a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a colorless oily matter was obtained. The resultant material was subjected to silica gel column chromatography (heptane) and recrystallization using Solmix A-11 (registered trademark) (Japan Alcohol Trading Co., Ltd.), and thus compound (1-B) was obtained as a white needle crystal (7.7 g).
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3](=O)[CH2:4][C:5]#[N:6].[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1>C(O)C>[F:1][C:2]([F:12])([C:3]1[CH:4]=[C:5]([NH2:6])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=2)[N:20]=1)[C:8]([F:9])([F:11])[F:10]
Reactant: N#CCC(=O)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(NN)cc1
Solvent: CCO
Product: Cc1ccc(-n2nc(C(F)(F)C(F)(F)F)cc2N)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Heat a mixture of 4,4,5,5,5-pentafluoro-3-oxo-pentanenitrile (4 g, 21.4 mmol) and p-tolyl-hydrazine (10 g, 64.1 mmol) in ethanol (20 mL) to 95° C. in a sealed tube apparatus for 15 hours. After cooling to room temperature, remove the solvent under reduced pressure to give a brown residue. Subject residue to silica gel chromatography eluting with ethyl acetate and hexanes to give the title compound (3.24 g, 52% yield, ES+(m/z) 292.1 [M+H]).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=O)OC(C)(C)C)[CH2:10][CH2:9]1.O.[OH-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:15][NH:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([OH:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN[C@H]1CC[C@H](O)CC1
Temperature: 25 °C

Procedure:
To a mixture of lithium aluminium hydride (9 g, 0.23 mol) in tetrahydrofuran (425 mL) was added slowly tert-butyl (trans-4-hydroxycyclohexyl)carbamate (intermediate 1, 10 g, 0.046 mol). The mixture was refluxed overnight. Once the mixture was cooled to room temperature, 9 ml of water, 9 ml of 4N NaOH solution and 18 ml of water were carefully and successively dropped. The organic solvent was removed under reduced pressure and the crude obtained was dissolved with chloroform and dried over magnesium sulphate. The filtrate was evaporated to dryness and co evaporated with hexane to give the title compound as a white solid (89%). This intermediate is also described in JMC, 1987, 30(2), p 313.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1cc(I)c(Cl)cn1
Reactant: Nc1ccccc1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: O=C(O)c1ccccc1Nc1cc(Cl)ncc1Cl
Temperature: 120 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
A mixture of 2,5-dichloro-4-iodopyridine (10 g, 36.5 mmol), 2-aminobenzoic acid (4.85 g, 35.4 mmol), DPEPhos [bis(2-diphenylphosphinophenyl)ether] (1.6 g, 2.97 mmol), palladium(II) acetate (160 mg, 0.713 mmol) and K3PO4 (20 g, 94 mmol) was degassed and heated at 120° C. (oil bath temp) for 20 h. After 20 h, LCMS showed there was 33% (relative to the desired product) starting material left. Added another 160 mg of Pd(OAc)2 to the mixture, and heated to 120° C. for another 24 h. LCMS showed conversion complete. The mixture was cooled to room temperature, followed by filtration, and washing with EtOAc. The solids were acidified to pH=7-8, followed by filtration. However, the mixture was a paste, and collected solids could not be dried completely. The solids (11 g) was acidified with 6N HCl to pH=1. The resulting paste was filtered, and washed with water and TBME. The solid was dried under vacuum over P2O5 for 2 days to give the title compound (7.32 g, 60.2% yield). MS: M(C12H8Cl2N2O2)=283.11, (M+H)+=283.8; 1H NMR (400 MHz, DMSO) ppm 13.6 (s, 1 H) 10.2 (s, 1 H) 8.3 (s, 1 H) 8.0 (d, 1 H) 7.6 (q, 2 H) 7.3 (s, 1 H) 7.2 (m, 1 H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(O[CH:6]([CH3:8])[CH3:7])=O.[CH2:15]([O:17][C:18]([C:20]1[N:21]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([OH:29])=[CH:24][CH:23]=2)=[O:19])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)C>O1CCCC1>[CH2:15]([O:17][C:18]([C:20]1[N:21]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH:6]([CH3:8])[CH3:7])=[CH:24][CH:23]=2)=[O:19])[CH3:16]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1cc2cc(OC(C)C)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropyl azodicarboxylate (0.15 ml, 0.75 mmol) was added to an anhydrous tetrahydrofuran (THF) solution (2.5 ml) of 5-hydroxy-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (175 mg, 0.48 mmol), triphenylphosphine (197 mg, 0.75 mmol), and 2-propanol (0.2 ml, 4.0 mmol), and stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-isopropoxy-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester as a colorless gum-like material (166.7 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].F[B-](F)(F)F.[O:15]=[N+:16]=[O:17].O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:16]([O-:17])=[O:15])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1C
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1C
Reaction time: 48 h

Procedure:
2-Methylanisole (20 g) in 500 ml dichloromethane chilled in an ice bath is treated with 27.2 g of nitronium tetrafluoroborate and stirred two days. The mixture is poured into water, the layers are separated, and the aqueous phase is washed with dichloromethane. The combined organic layers are dried, filtered, stripped, and chromatographed on silica gel with 9:1 to 8:2 hexane:ethyl acetate to give 2-methyl-4-nitroanisole. NMR (CDCl3): δ2.3 (3H,s), 3.9 (3H,s), 6.9 (1H,d), 8.0 (1H,d), 8.1 (1H,d of d).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:29]([F:32])([F:31])[F:30])[O:17][N:16]=[C:15]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](F)=[CH:20][CH:19]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>CN(C=O)C>[N:1]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:15]2[CH2:14][C:13]([C:8]3[CH:7]=[C:6]([Cl:5])[CH:11]=[C:10]([Cl:12])[CH:9]=3)([C:29]([F:32])([F:30])[F:31])[O:17][N:16]=2)=[CH:19][CH:20]=1)=[N+:2]=[N-:3]
Reactant: Fc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Sodium azide (3.3 g) is added to a solution of 5-(3,5-dichloro-phenyl)-3-(4-fluoro-naphthalen-1-yl)-5-trifluoromethyl-4,5-dihydro-isoxazole (10.7 g) in DMF (50 ml). After 20 hours at 80° C. another portion of sodium azide is added (3.3 g) and the reaction mixture is stirred for 20 hours at 80° C. The solution is cooled to room temperature and the volume concentrated to 10 ml in vacuo. Water and ethyl acetate are added and the precipitate is collected after filtration to yield 3-(4-azido-naphthalen-1-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole as a beige solid: 183-185° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:2]1.C(Cl)(=O)OCC.[CH3:17][O:18][C:19]1[CH:24]=[C:23]2[C:25]([NH2:35])=[N:26][C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:28][C:22]2=[CH:21][C:20]=1[O:36][CH3:37]>C(N(CC)CC)C.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[N:26]=[C:25]([NH2:35])[C:23]4[C:22](=[CH:21][C:20]([O:36][CH3:37])=[C:19]([O:18][CH3:17])[CH:24]=4)[N:28]=3)[CH2:30][CH2:31]2)=[O:10])=[CH:2]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(O)C=Cc1ccoc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccoc4)CC3)nc(N)c2cc1OC
Reaction time: 3 h
Yield: 59 %

Procedure:
To a mixture of 276 mg. (2 mM) of 3-(furan-3-yl)acrylic acid, and 242 mg. (2.4 mM) of triethylamine in 10 ml. of ethyl acetate was added dropwise under ice-cooling a solution of 260 mg. (2.4 mM) of ethyl chlorocarbonate in 5 ml. of ethyl acetate. The resulting mixture was stirred for 3 hours and 761 mg. (2 mM) of 2-piperazine-4-amino-6,7-dimethoxyquinazoline and 484 mg. (4.8 mM) of triethylamine were odded thereto. Stirring was continued at room temperature for further one day. The precipitate thus separated was recovered by filtration and washed well with water to give 480 mg. of the desired product.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:23][CH2:22][C@H:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30](=[O:32])[CH3:31])[CH2:26][CH2:25]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:17])[CH3:14])[C:6](C(F)(F)F)=[CH:7][CH:8]=1.[ClH:43]>CCOCC>[ClH:43].[F:1][C:2]([F:41])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:23][CH2:22][C@H:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30](=[O:32])[CH3:31])[CH2:28][CH2:29]3)[CH2:20][C@@H:19]2[C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:17])[CH3:14])[CH:6]=[C:7]([C:2]([F:42])([F:41])[F:1])[CH:8]=1
Reactant: CC(=O)N1CCN([C@H]2CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)ccc3C(F)(F)F)[C@@H](c3ccc(F)cc3)C2)CC1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)N1CCN([C@H]2CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3)C2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 18b (20 mg) in dry Et2O (1 mL) was treated at −8° C. with hydrochloric acid (1M in Et2O—0.5 mL). The resulting mixture was stirred at 0° C. for 10 minutes, then filtered; the filtrate was triturated with dry pentane (2×2 mL) to give the title compound as a whitish solid (14.7 mg).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH:4]=[N:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[OH:17][C:7]1([C:5]2[CH:4]=[N:3][CH:2]=[N:1][CH:6]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: OC1(c2cncnc2)CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2cncnc2)CC1
Yield: 97 %

Procedure:
A solution of 8-pyrimidin-5-yl-1,4-dioxaspiro[4,5]decan-8-ol (0.14 g, 0.59 mmol) in 10 mL of THF/1 N HCl (1:1) was stirred for 24 h at room temperature. The mixture was treated with Na2CO3 to pH 8 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.11 g of 4-hydroxy-4-pyrimidin-5-ylcyclohexanone in 79% yield. MS (EI) calcd: (M+H)+=192.1. Found: 192.1.
Reaction SMILES: [Br:1][C:2]1=[C:3]([Br:9])[C:4]([O:6][C:7]1=[O:8])=O.FC(F)(F)C([O-])=O.[O:17]=[C:18]1[NH:22][CH:21]2[CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH3+:41])=[O:31])[S:24][CH2:25][CH:20]2[NH:19]1.C1(C)C=CC=CC=1.CO.C(Cl)Cl>CC(O)=O>[Br:9][C:3]1[C:4](=[O:6])[N:41]([CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][NH:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH:23]2[CH:21]3[NH:22][C:18](=[O:17])[NH:19][CH:20]3[CH2:25][S:24]2)[C:7](=[O:8])[C:2]=1[Br:1]
Reactant: O=C1OC(=O)C(Br)=C1Br
Reactant: [NH3+]CCOCCOCCNC(=O)CCCCC1SCC2NC(=O)NC21
Agent: O=C([O-])C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCCOCCOCCN1C(=O)C(Br)=C(Br)C1=O
Temperature: 170 °C
Yield: 47.6 %

Procedure:
Dibromomaleic anhydride (108 mg, 0.42 mmol, 1 eq) was added in one portion to a solution of 2-(2-(2-(5-(2-oxo-1,3,3a,4,6,6a-hexahydrothieno(3,4-d)imidazol-6-yl)pentanoylamino)ethoxy)ethoxy)ethylammonium 2,2,2-trifluoroacetate (205 mg, 0.42 mmol, 1 eq) in AcOH (10 mL) and the reaction mixture heated to 170° C. for 2 h. Upon cooling to 21° C. toluene was added and the AcOH azeotropically removed in vacuo (×2) to give crude product. Column chromatography (gradient 2-7% MeOH/CH2Cl2) yielded the desired compound as a white solid (123 mg, 0.20 mmol, 48% yield). m.p. 100-102° C.; [α]D20.0+71.0 (c 0.15, MeOH); 1H NMR (600 MHz, CD3OD) δ 4.53 (dd, J=5.0, 8.0 Hz, 1H, NHC(O)NHCH), 4.34 (dd, J=5.0, 8.0 Hz, 1H, NHC(O)NHCH), 3.82 (t, J=5.5 Hz, 2H, OCH2), 3.70 (t, J=5.5 Hz, 2H, OCH2), 3.63 (m, 2H, OCH2), 3.59 (m, 2H, OCH2), 3.53 (t, J=5.5 Hz, 2H, NCH2), 3.37 (t, J=5.5 Hz, 2H, NCH2), 3.24 (dt, J=5.0, 8.0 Hz, 1H, SCH), 2.96 (dd, J=5.0, 13.0 Hz, 1H, SCHH), 2.73 (d, J=13.0 Hz, 1H, SCHH), 2.26 (t, J=7.5 Hz, 2H, NHC(O)CH2CH2CH2), 1.74 (m, 4H, CH2CH2CH2), 1.49 (quintet, J=7.5 Hz, 2H, CH2CH2CH2); 13C NMR (150 MHz, CD3OD) δ 174.83 (s), 164.71 (s), 164.06 (s), 129.00 (s), 69.80 (t), 69.72 (t), 69.24 (t), 67.19 (t), 61.97 (d), 60.22 (d), 55.64 (d), 39.67 (t), 39.03 (t), 38.56 (t), 35.42 (t), 28.39 (t), 28.11 (t), 25.47 (t); IR (MeOH) 2970, 1724, 1365, 1217 cm−1; HRMS (ES) calcd for C20H28N4O6NaSBr2 [M+Na]+ 631.9916, observed 631.9937.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]([OH:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[CH:15]([O:18][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:17])[CH3:16]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 120 °C

Procedure:
A mixture of 2.13 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.64 mmol Cu(I)Br in 5 ml triethylamine and 25 ml isopropanol was heated to 120° C. for 16 h in a sealed tube. The volatiles were removed in vacuo and the residue was taken up in 70 ml 1 N HCl. Extraction with ethyl acetate, drying of the combined organic fractions and evaporation yielded a residue which was purified by reversed phase preparative HPLC eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded the title compound. MS (m/e): 257.0 ([M−H]−, 100%)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1S,3S)-3-aminocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f64) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16]Br)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][N:18]=[N+:19]=[N-:20])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=N\OCCN=[N+]=[N-])c1csc(N)n1
Yield: 96.3 %

Procedure:
1 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-bromoethoxy)imino]-acetate in 20 ml of dimethylformamide is warmed to 50° C. for 12 hours with 9.5 g of sodium azide. The mixture is diluted with ethyl acetate, washed three times with water, dried over magnesium sulphate and evaporated. After recrystallization from acetone/isopropanol, there is obtained 0.85 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-azidoethoxy)imino]-acetate of melting point 123°-124° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]([NH:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:13])[CH:11]=[CH2:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([C:17]2[CH:16]=[C:15]([NH:14][C:10](=[O:13])[CH:11]=[CH2:12])[CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C=CC(=O)Nc1cccc(B(O)O)c1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Br)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
5-bromo-2,4-dichloropyrimidine (100 mg, 0.439 mmol), (3-acrylamidophenyl)boronic acid (50 mg, 0.262 mmol) and triphenylphosphine (4 mg, 0.018 mmol) were dissolved in a mixture of toluene (8 mL) and potassium carbonate (14 mg, 0.043 mmol), after which palladium(II) acetate (2 mg, 0.009 mmol) was added. The reaction mixture was allowed to stir overnight at 40° C. The reaction was monitored by TLC, and after completion of the reaction the solvent was removed in vacuo. The crude material was purified by flash chromatography (EtOAc/Hexane 20%) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.64 (s, 1H), 7.38-7.29 (m, 2H), 6.85 (m, 1H), 6.38-6.21 (m, 2H), 5.69 (dd, 1H, J=1.6 & 10.0 Hz). ESI-MS: m/z 339.90 [M+H]+.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][C:8]1=[O:23].FC(F)(F)C(O)=O>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][C:8](=[O:23])[N:7]2[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc(=O)n(CC2OCCO2)c2cc(OC)ccc12
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(=O)n(CC=O)c2cc(OC)ccc12
Reaction time: 14 h
Yield: 116 %

Procedure:
To 0.19 g of methyl 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate, 2 mL of 90% aqueous trifluoroacetic acid solution was added and stirred for 14 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.19 g of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate. (2) To 3 mL of a dichloromethane solution containing 0.17 g of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate, 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 34 μL of acetic acid were added and stirred for 1 hour. To the reaction mixture, 0.19 g of sodium triacetoxyborohydride was added and stirred for 1 hour. Ethyl acetate and aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=100:1] to give 0.25 g of methyl 1-(2-(4-((tert-butoxycarbonyl) (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate as a brown oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](O)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:21].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([Cl:21])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1nc(O)c2sccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(Cl)c2sccc2c1O
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 143.5 %

Procedure:
A mixture of 4,7-dihydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (267 mg, 1 mmol), POCl3 (217 mg, 1.4 mmol), and toluene (4 ml) was heated in a microwave oven at 140° C. for 15 min. The same procedure was repeated with a second batch. Both batches were combined, conc. aqueous NaHCO3 (40 ml) and EtOAc (40 ml) were added and the mixture was stirred vigorously for 45 min. The organic layer was then separated, dried over MgSO4 and concentrated in vacuo to give a tan solid (410 mg). Purification by flash column chromatography on silica gel using CH2Cl2:EtOAc=9:1 as the eluent yielded the title compound as a tan solid (297 mg, first major fraction). MS-(−)-ion: M−1=284.3.