Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:28][C:29]([C:31]1[CH:35]=[C:34]([OH:36])[N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:32]=1)=[O:30])[C:10](=[O:27])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:50][O:51][C:52]([C:54]1[O:55][C:56]([CH2:59]Cl)=[CH:57][CH:58]=1)=[O:53]>CN(C=O)C.C(OCC)(=O)C>[CH3:50][O:51][C:52]([C:54]1[O:55][C:56]([CH2:59][O:36][C:34]2[N:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:32]=[C:31]([C:29](=[O:30])[NH:28][C@H:9]([C:10]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=4)[CH2:15][CH2:16]3)=[O:27])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:43])[CH:35]=2)=[CH:57][CH:58]=1)=[O:53]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(O)n(-c2ccccc2)n1)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N3CCN(c4cccc(C(F)(F)F)c4)CC3)nn2-c2ccccc2)o1

Procedure:
180 mg of (S)-4-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-5-oxo-5-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]-pentanoic acid tert-butyl ester dissolved in 4 ml DMF was treated with 293 mg of cesium carbonate and 78 mg of Methyl-5-(chlormethyl)furan-2-carboxylate. After 3 h at 70° C. the mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution. Drying of the organic layer over sodium sulfate gave crude 5-(5-{(S)-3-tert-Butoxycarbonyl-1-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-propylcarbamoyl}-2-phenyl-2H-pyrazol-3-yloxymethyl)-furan-2-carboxylic acid methyl ester which was used for the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Br:12])[C:5]2[O:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21].O>CS(C)=O.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([Br:12])[C:5]2[O:9][C:8]([NH:10][C:23]([NH:22][CH2:20][CH3:21])=[O:24])=[N:7][C:6]=2[CH:11]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(Br)cc(Br)c2o1
Solvent: C1COCCO1
Solvent: O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(Br)cc(Br)c2o1
Temperature: 60 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
A solution of 5,7-dibromo-1,3-benzoxazol-2-amine 1(1050 mg; 3.60 mmol) in DMSO (0.7 mL) and dioxane (16 mL) was treated with triethylamine (980 mg, 9.7 mmol) and ethyl isocyanate (767 mg, 10.79 mmol). The reaction was stirred at 60° C. for 24 h. After that time an additional batch of ethyl isocyanate (400 mg, 6 mmol) and triethylamine (500 mg, 5 mmol) were added and the mixture stirred at 60° C. further 24 h. Water was then added and the solid formed was filtrated, rinsed with water and then triturated with EtOAc to give the desired product as a white-off solid (m=950 mg; yield: 73%). 1H NMR (DMSO) δ 11.25 (br s, 1H), 8.16-8.10 (m, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 3.30-3.22 (m, 2H), 1.13 (t, J=7.2 Hz, 3H). ESI-MI m/z [M+H]+: 293.1. 1Prepared according to the method described in J. Pharm. Sci (1964) Vol. 53 p 538-544.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Br:23][C:24]1[C:29](=O)[N:28]([CH3:31])[C:27]2[N:32]([C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[N:33]=[CH:34][C:26]=2[CH:25]=1>C1(C)C=CC=CC=1>[Br:23][C:24]1[C:29](=[S:10])[N:28]([CH3:31])[C:27]2[N:32]([C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[N:33]=[CH:34][C:26]=2[CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Solvent: Cc1ccccc1
Product: Cn1c(=S)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Temperature: 125 °C
Yield: 41.9 %

Procedure:
A mixture of Lawesson's reagent (297 mg, 0.73 mmol) and 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (125 mg, 0.68 mmol) in toluene (8 mL) was heated to 125° C. for 15 h. The solvent was removed under reduced pressure (rotary evaporator) and the crude residue was purified on the ISCO 40 g column (5-40% EtOAc in hexanes) affording the title compound (101.6 mg) as a bright yellow crystalline solid. MS (ESI, pos.ion) m/z: 355.9/357.9 (M+1).
Reaction SMILES: C(O)CC.Cl[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>O>[N:18]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(OCCCCl)cc1
Solvent: CCCO
Solvent: O
Product: N#Cc1ccc(OCCCn2ccnc2)cc1
Yield: 82.3 %

Procedure:
To 30 ml of n-propanol, there were added 2.695 g of 4-(3-chloropropoxy)benzonitrile and 10.21 g of imidazole and the resulting mixture was heated under reflux for 24 hours. After concentration of the reaction mixture, water was added to the residue obtained, followed by extraction with chloroform, washing of the resulting extract with water and then drying the same. After concentration of the extract, the residue obtained was recrystallized from a mixture of ether and n-hexane, followed by addition of n-hexane, filtration and drying to give 2.575 g (yield 75.3%) of 4-[3-(1H-imidazolyl)propoxy]benzonitrile having a melting point of 60.0°-61.5° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=1)C.[NH3:20]>C1COCC1>[NH2:20][C:11]1[N:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:19])[CH:14]=[CH:13][N:12]=1
Reactant: N
Reactant: CCOC(=O)CCCCc1ccnc(S(C)(=O)=O)n1
Solvent: C1CCOC1
Product: Nc1nccc(CCCCC(=O)O)n1
Reaction time: 4 h

Procedure:
A solution of 26-4 (0.19 g, 0.67 mmol) in THF (5 mL) was cooled to 0° and saturated with NH3 gas. The mixture was stirred at 0° for 4 h, then evaporated and the residue partitioned between EtOAc and sat. NaHCO3. The organic layer was dried filtered and concentrated to give the amino ester 26-5.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[N:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[OH:17][C:15]([CH3:18])([CH3:16])[CH2:14][NH:13][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][N:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1ccncc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)CNC(=O)c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 10.6 %

Procedure:
A mixture of 3-nitroisonicotinic acid (1.75 g, 10.1 mmol), 1-amino-2-methylpropan-2-ol (968 ul, 10.1 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (4.86 g, 15.1 mmol) and triethylamine (4.9 ml, 35.3 mmol) in tetrahydrofurane (60 ml) was stirred over the week-end at rt. The reaction mixture was diluted with ethyl acetate, washed with water, with brine, dried with magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography using a CH2Cl2/MeOH gradient as eluent, providing the title compound as off-white solid (255 mg, 11%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:31]=[CH2:32].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:32]=[CH:31]/[CH2:30][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 100 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (100 mg, 0.184 mmol) in MeCN (5 mL) in a pressure vessel is added allylbenzene (22 mg, 0.184 mmol), Pd(OAc)2 (3 mg) and triethylamine (186 mg, 1.84 mmol) and the mixture is heated at 100° C. for 10 h. The solvent is evaporated and the residue is purified by flash chromatography using a gradient of 10% to 40% EtOAc/hexane as eluent to give the title compound as a yellow foam.
Reaction SMILES: ClC1C=C2C(=CC=1)N([N+:11]([O-:13])=[O:12])C(C(OCC)=O)=C2.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[C:27](Cl)[CH:28]=1)[NH:25][C:24]([C:30]([OH:32])=[O:31])=[CH:23]2>>[N+:11]([C:21]1[C:20]([Cl:19])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[C:24]([C:30]([OH:32])=[O:31])[NH:25]2)([O-:13])=[O:12]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1[N+](=O)[O-]
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2[nH]1
Product: O=C(O)c1cc2c([N+](=O)[O-])c(Cl)ccc2[nH]1

Procedure:
The title compound was prepared by hydrolysis of ethyl 5-chloro-nitro-1H-indole-2-carboxylate as described for the preparation of 5,7-dichloro-1H-indole-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1/[C:22](=[CH:27]\[O:28][CH3:29])/[C:23]([O:25][CH3:26])=[O:24].[F-].[Cs+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.C(OCC)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2/[C:22](=[CH:27]\[O:28][CH3:29])/[C:23]([O:25][CH3:26])=[O:24])[N:3]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1ncnc(Cl)n1
Yield: 65.3 %

Procedure:
To a stirred solution of 2,6-dichloro-1,3,5-triazine (0.3 g, 2 mmol; made according to R L N Harris, Synthesis, 1981, 907) and potassium carbonate (0.28g, 2 mmol) in dry acetonitrile (25 ml) at 0° C. under an atmosphere of nitrogen was added dropwise a solution of (E)-methyl 2-(2-hydroxyphenyl)-3-methoxypropenoate (0.42 g, 2 mmol) in dry acetonitrile (7 ml). Anhydrous caesium fluoride (0.30 g, 2 mmol) and a catalytic amount of 18-crown-6 were added with stirring and the temperature was allowed to rise to room temperature. After stirring overnight, the reaction mixture was filtered and evaporated to leave a yellow/orange paste. Chromatography (eluent diethyl ether) afforded (E)-methyl 2-[2-(4-chloro-1,3,5-triazin-2-yloxy)phenyl]-3-methoxypropenoate (0.42 g) as a white solid, m.p. 137-140° C.; IR max. 1704, 1631 cm-1 ; 1H NMR (CDCl3) δ3.63(3H,s); 3.75(3H,s); 7.19-7.29(1H,m); 7.31-7.45(3H,m); 7.47(1H,s); 8.74(1H,s) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:25]=[CH:24][C:13]3[C:14]4([CH3:23])[CH:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[C:6]([C:26]([F:29])([F:28])[F:27])[CH:5]=1)([O-:3])=[O:2].[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=4[C:26]([F:29])([F:27])[F:28])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC12CCC(=O)NC1CCc1cc(-c3ccc([N+](=O)[O-])cc3C(F)(F)F)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc([N+](=O)[O-])cc4C(F)(F)F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-10bR)-8-(4-nitro-2-trifluoromethylphenyl)-10b-methyl-1,2,3,4, 4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide ! 0.022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 35 mg (70%) of the title compound as a white solid. mp 128°-130°. FDMS: m/e=418.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[C:5]([F:16])=[C:4]([NH:17][NH2:18])[N:3]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][NH:18][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[C:5]([F:16])=[C:6]([N:8]([CH3:15])[CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[N:7]=1
Reactant: CN(Cc1nccs1)c1nc(Cl)nc(NN)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(Cc1nccs1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Reaction time: 8 h

Procedure:
2-Chloro-5-fluoro-6-hydrazino-N-methyl-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine (assumed dihydrochloride) (0.9034 g, 2.509 mmol) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (1.299 g, 3.01 mmol) were dissolved in DMF (13 mL). NMM (1.655 mL, 15.05 mmol) was added, followed by HOAt (0.4095 g, 3.01 mmol) and EDC (0.577 g, 3.01 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[methyl(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a red sticky material. LCMS: (M+H)+=570.2.
Reaction SMILES: C[O:2][C:3](=[O:49])[C:4]([CH3:48])([CH3:47])[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@H:6]([CH2:5][C:4]([CH3:48])([CH3:47])[C:3]([OH:49])=[O:2])[CH2:11]2)=[CH:17][CH:16]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 8.62 g of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid methyl ester in 20 ml tetrahydrofuran and 50 ml ethanol are added 60 ml of a 20% sodium hydroxide solution. The reaction mixture is stirred for 4 hours at 65° C. The organic solvents are evaporated under reduced pressure and the remaining solution is acidified with 6M aqueous hydrochloric acid until pH 2. This mixture is extracted with 200 ml ethyl acetate (3×). The combined organic layers are washed with brine and dried with sodiumsulfate. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless foam. Rf=0.27 (EtOAc-heptane 3:1); Rt=5.10.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([C:11]1[S:12][C:13]([C:17]#[N:18])=[C:14]([NH2:16])[N:15]=1)=O>C(#N)C>[C:1]1([S:7][C:11]2[S:12][C:13]([C:17]#[N:18])=[C:14]([NH2:16])[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1nc(N)c(C#N)s1
Reactant: Sc1ccccc1
Solvent: CC#N
Product: N#Cc1sc(Sc2ccccc2)nc1N
Reaction time: 8 h

Procedure:
15.5 ml (16.5 g) of thiophenol are added to a suspension of 9.35 g of 2-methylsulphinyl-4-amino-5-cyanothiazole, prepared according to example I, in 250 ml of acetonitrile, while stirring. After stirring at room temperature for another 30 minutes and leaving to stand overnight, the mixture is filtered with charcoal, after which the filtrate is evaporated. The residue is taken up in methylene chloride, after which the resulting solution is washed, successively with 2N sodium hydroxide solution and water, dried, filtered and diluted with isopropanol. After evaporating the methylene chloride the desired product crystallises in a yield of 7.62 g; m.p. 176°-18° C.; Rf (CH2Cl2) 0.15.
Reaction SMILES: [CH:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=2[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=2[C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccc(C2CCCC2)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 4-cyclopentyl-3-(trifluoromethyl)benzaldehyde (0.25 g, 1.032 mmol) in ethanol (2.5 mL) was added sodium borohydride (0.047 g, 1.238 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was quenched with water, acidified with 6 N HCl, diluted with more water and extracted with CH2Cl2. The CH2Cl2 layer was washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (0.22 g). LCMS m/z=227.5 [M−H2O+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.72 (m, 4H), 1.77-1.89 (m, 2H), 1.93-2.05 (m, 2H), 3.19-3.28 (m, 1H), 4.52 (d, J=6 Hz, 2H), 5.28 (t, J=5.6 Hz, 1H), 7.52-7.6 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Product: Cc1ccc(-c2ccc(S(=O)(=O)NCCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-methylphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 20.8, 22.6, 28.9, 32.0, 42.6, 60.5, 126.9, 127.0, 127.3, 129.7, 135.7, 138.0, 139.0 and 143.7.
Reaction SMILES: [N:1]1[CH:6]=[C:5](C(O)=O)[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=O.[CH3:13][O:14]C1C=C(C=C(OC)C=1OC)C(O)=O>>[N:1]1[C:2]([CH2:10][OH:12])=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:13][OH:14]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Product: OCc1cccc(CO)n1

Procedure:
Pyridine 2,5-dicarboxylic acid is reacted in a process similar to that utilized in the reaction of 3,4,5-trimethoxybenzoic acid set forth in the first two portions of the procedure of Example I so as to produce the corresponding mixed anhydride that is subjected to the catalytic hydrogatation to obtain pyridine 2,6-dimethanol.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:27][CH2:26][N:25](C(OCC3C=CC=CC=3)=O)[CH2:24][CH:23]=2)=[CH:18][CH:17]=1.O[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.[Pd]>[NH:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:44][CH2:43]3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ccc(O)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: [Pd]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCNCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
DIAD (5.20 mL, 26.39 mmol) was added dropwise to benzyl 4-(4-hydroxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (6.80 g, 21.99 mmol), tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (5.91 g, 24.19 mmol) and triphenylphosphine (6.92 g, 26.39 mmol) in THF (100 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated to dryness then the residues were dissolved in ether (50 mL) and stirred for 10 minutes at ambient temperature. The resulting precipitate was removed by filtration. The filtrate was washed with water (50 mL) and saturated brine (50 mL), then dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM (50 mL) and the solution was washed with 2M NaOH (50 mL), followed by saturated brine (50 mL), then dried over MgSO4, filtered, evaporated and purified by flash silica chromatography, elution gradient 30 to 70% ethyl acetate in isohexane. Fractions were evaporated to a gum, which was dissolved in MeOH (150 mL) and stirred with 5% palladium on carbon (50% wet, 1.907 g, 0.45 mmol) under an atmosphere of hydrogen at 5 bar and 25° C. for 16 hours. The catalyst was removed by filtration, washed with MeOH and the solvents were evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% 2M ammonia in methanol in DCM. Fractions containing the desired product were evaporated to dryness to give tert-butyl 4-[3-[4-(piperidin-4-yl)phenoxy]propyl]piperazine-1-carboxylate (4.95 g, 56%) as a solid.
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[C:12]=2[N:11]2[CH2:31][CH2:32][N:33]([CH3:36])[C:34](=[O:35])[C:10]=12)C1C=CC=CC=1.[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>CN(C=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:34](=[O:35])[N:33]([CH3:36])[CH2:32][CH2:31][N:11]4[C:12]=3[C:13]([N:27]([CH3:37])[C:28](=[O:30])[CH3:29])=[N:14]2)=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)Nc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1nn(Cc2ccc(F)cc2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-[10-(benzyloxy)-2-(4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazin-4-yl]acetamide (0.13 g, 0.27 mmol) in anhydrous DMF (5 mL), a solution of lithium bis(trimethylsilyl)amide (0.4 mL, 0.4 mmol; 1 M in THF) was added. The mixture was stirred at room temperature for 10 minutes, treated with iodomethane (25 μL, 0.40 mmol), and stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and the residue partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The title compound was debenzylated in accordance with the procedure set forth in Example 62, step 12.