Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[O:7][C:6]([C:9]2[CH:10]=[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)([CH3:8])[CH2:5][O:4]1)[CH3:2].Cl.[NH2:26][OH:27]>>[CH2:1]([CH:3]1[O:7][C:6]([C:9]2[CH:10]=[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=[N:26][OH:27])[CH3:23])=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)([CH3:8])[CH2:5][O:4]1)[CH3:2]
Reactant: CCC1OCC(C)(c2cccc(Sc3ccc(C(C)=O)cc3)c2)O1
Reactant: NO
Agent: Cl
Product: CCC1OCC(C)(c2cccc(Sc3ccc(C(C)=NO)cc3)c2)O1
Yield: 31 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-[3-(2-ethyl-4-methyl-1,3-dioxolan-4-yl)phenylthio]acetophenone was reacted with hydroxylamine hydrochloride to give 4'-[3-(2-ethyl-4-methyl-1,3-dioxolan-4-yl)phenylthio]acetophenone oxime in 31% yield as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]=[C:18]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+].Cl>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]=[C:18]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)[O-]
Reactant: O=C(O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(C(=O)c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)c2cc(CCNS(=O)(=O)c3ccc(Cl)cc3)cc(CCC(=O)O)c2)cc1
Reaction time: 20 h
Yield: 41 %

Procedure:
A solution of 3-[2-[(4-chlorophenyl)sulphonylamino]ethyl]-5-(4-fluorobenzoyl)benzenepropanoic acid (0.25 g) and sodium methanesulphinate (0.61 g) in dimethylsulphoxide (1.0 ml) was heated at 130° C. under dry nitrogen for 30 hours. Additional sodium methanesulphinate (1.2 g) was added and heating was continued for a further 20 hours. The solution was diluted with water, acidified with 2N hydrochloric acid and extracted several times with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (97:3) as eluent. The product fractions were combined and evaporated to give the title compound as a foam (0.115 g), Rf 0.25(SS 8). Found: C,54.96; H,4.53; N,2.18. C25H24CINO7S2 requires: C,54.59; H,4.40; N,2.55%.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:19])[CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH:19][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH2:17][CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[C@H](N)c1nc2cccnc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccnc2n1-c1ccccc1
Temperature: 90 °C
Yield: 21.6 %

Procedure:
A mixture of (S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)propylamine (430 mg, 1.70 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (560 mg, 2.39 mmol) and DIPEA (0.54 mL, 3.07 mmol) in n-butanol (3 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) to afford 169 as a white solid (136 mg, 22%). LCMS (Method K): RT 2.89 min [M+H]+ 371.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.91 (1H, s), 8.30-7.70 (5H, m), 7.68-7.21 (6H, m), 5.42 (1H, s), 2.01 (2H, bs), 1.01-0.71 (3H, m).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[C:10]([OH:15])(=[O:14])[C:11]([OH:13])=[O:12].[C:16]1([CH:22]([CH2:25][CH3:26])[CH2:23][OH:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:10]([OH:15])(=[O:14])[C:11]([OH:13])=[O:12].[C:16]1([CH:22]([CH2:25][CH3:26])[CH2:23][O:24][C:11]([N:6]2[CH2:7][CH2:8][C:9]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:5]2)=[O:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC(CO)c1ccccc1
Reactant: c1nc2c([nH]1)CCNC2
Agent: O=C(O)C(=O)O
Product: CCC(COC(=O)N1CCc2[nH]cnc2C1)c1ccccc1

Procedure:
The compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-phenyl-1-butanol oxalate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[F-].[Cs+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:17][C@H:18]1[O:20][CH2:19]1)(=O)=O.O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:17][C@H:18]1[O:20][CH2:19]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
2-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF. Cesium fluoride (3.02 g, 19.9 mmol) was added to the reaction. The reaction mixture was stirred for 1 hour at room temperature and (S)-glycidyl nosylate (1.71 g, 6.6 mmol) was added. The reaction was stirred for 16 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO4 and evaporated. The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent to give (S)-glycidyl o-nitrophenyl ether (1.21 g, 90% yield, m.p. 46-47° C.) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].C[O-].[Na+].[C:29](=O)([O:32]C)[O:30][CH3:31]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[C@@H:11]3[C:29]([O:30][CH3:31])=[O:32])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)OC
Reactant: CCCOc1ccc2c(c1)C(=O)C[C@H]2c1ccc2c(c1)OCO2
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCOc1ccc2c(c1)C(=O)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Temperature: 40 °C
Yield: 39.8 %

Procedure:
A 100 mL three-necked flask under nitrogen was charged with (S)-3-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-inden-1-one (1.5 g, 4.84 mmol), toluene (20 mL), 60% NaH suspension (213 mg, 5.3 mmol), NaOMe (288 mg, 5.3 =mmol), and dimethyl carbonate (2.5 mL, 29 mmol). The solution was warmed to 40 ° C. for 3 h, cooled to 0° C., quenched with 3 M AcOH (0.5 mL) and diluted with H2O (50 mL) and EtOAc (50 mL). The organic phase was washed with brine (50 mL), dried (MgSO4) and concentrated. The crude material was triturated with EtOAc/hexane (1:3, 50 mL) affording (1S-trans)-methyl 1-(1,3-benzodioxol-5-yl) -2,3-dihydro-3-oxo-5-propoxy-1H-indene-2-carboxylate as a pale yellow solid (710 mg, 73% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH:38]=[CH2:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:40]>O1CCOCC1>[NH2:40][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH:38]=[CH2:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Solvent: C1COCCO1
Product: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(N)ncnc21
Temperature: -78 °C

Procedure:
The compound from Step B (80, mg) was dissolved in the minimum amount of 1,4-dioxane and placed in a stainless steel bomb. The bomb was cooled to −78° C. and liquid ammonia was added. The bomb was sealed and heated at 90° C. for 24 h. The ammonia was allowed to evaporate and the residue concentrated to a white solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].Cl.[N:31]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=O)=[CH:43][CH:42]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:49]=[CH:48][C:44]([CH2:45][CH2:2][CH2:1][NH:3][C:4]3[C:5]([CH:13]4[CH2:22][CH2:21][C:20]5[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=5[CH2:14]4)=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)=[CH:43][CH:42]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(CCCN2CCCCCC2)cc1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1cc3c(cc1NCCCc1ccc(CCCN4CCCCCC4)cc1)OCO3)C2
Yield: 58.5 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(3-azepan-1-ylpropyl)benzoic acid hydrochloride (80 mg) according to an analogous synthetic method to Example 337 described below, the title compound (32 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1[OH:20]>B(F)(F)F.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:18]2[CH:19]=[C:13]([Cl:12])[C:14]([OH:20])=[CH:15][C:16]=2[OH:17])=[O:11])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(Cc1ccc(Br)cc1)c1cc(Cl)c(O)cc1O
Reaction time: 2 h

Procedure:
This compounds was synthesised in the same manner as described above. 4-Bromophenylacetic acid (7.44 g, 34.6 mmol), 4-chlororesorcinol (5 g, 34.6 mmol), boron trifloride etherate (30 ml). After standing for two hours an orange precipitate formed. This was purified by flash chromatography to give the required compound as an off white solid (10.5 g, 89%); Rf 0.9 hexane/ethyl acetate (20/80).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-:21][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[CH2:28]([O:30][C:31]([C:33]1[CH:37]=[CH:36][N:35]([CH:38]([CH3:40])[CH3:39])[C:34]=1[CH3:41])=[O:32])[CH3:29]>CC#N.O>[CH2:28]([O:30][C:31]([C:33]1[CH:37]=[CH:36][N:35]([CH:38]([CH3:40])[CH3:39])[C:34]=1[CH:41]=[O:21])=[O:32])[CH3:29]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccn(C(C)C)c1C=O
Reaction time: 0.17 h

Procedure:
CAN (979 mmol) was added to a mixture of 1-isopropyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester [224180-70-5] (218 mmol) in CH3CN (1800 mL) and water (360 mL) at 15° C. After 10 min, the reaction mixture was quenched with ice and extracted with MTBE. The organic phase was successively washed with a saturated aqueous solution of NaHCO3 (2×) and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a yellow oil. tR: 4.43 min (HPLC 1); ESI-MS: tR=1.06 min, [M+H]+ 210 (LC-MS 1); TLC: Rf=0.21 (1:9 EtOAc/heptanes).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH:15]([NH:20]S(C(C)(C)C)=O)[C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C:8]3(OCC[O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>C(O)(=O)C.C(O)C>[NH2:20][CH:15]([C:5]1([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:6][CH2:7][CH:8]([OH:9])[CH2:13][CH2:14]1)[C:16]([F:17])([F:18])[F:19]
Reactant: CC(C)(C)S(=O)NC(C(F)(F)F)C1(CC2CC2)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(C(F)(F)F)C1(CC2CC2)CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-methyl-propane-2-sulfinic acid [1-(8-cyclopropylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-2,2,2-trifluoro-ethyl]-amide (20, 1.00 g, 2.52 mmol) in 80% acetic acid (10 mL) was heated in a microwave oven for 10 min at 130° C. Then, the reaction mixture was slowly dropped into cold saturated sodium bicarbonate solution (150 mL), stirred for 30 min at room temperature and extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo to give the crude ketone, which was taken up in ethanol (20 mL), cooled to 0° C. and treated with sodium borohydride (190 mg, 5.03 mmol, 2.0 eq.). After the reaction went to completion, the mixture was poured onto water (20 mL) and extracted three times with dichloromethane. The organic layers were concentrated in vacuo and the residue was dissolved in a mixture of 2-propanol (15 mL) and 6N aqueous hydrochloric acid (5 mL). After stirring overnight at room temperature, another 5 mL of 6N aqueous hydrochloric acid were added and the mixture was warmed to 50° C. for 1 h. The reaction mixture was concentrated in vacuo and lyophilized twice from water to give the title compound (21) as racemic mixture of diastereoisomers as its hydrochloride. Rt=0.73 min, 0.82 min (Method B). Detected mass: 252.3 (M+H+).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:56]([CH2:59][CH3:60])=[C:57]=[O:58]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:59]([NH:56][C:57](=[O:58])[O:39][C@H:36]1[CH2:37][CH2:38][C@@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)[CH3:60]
Reactant: CCN=C=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)O[C@H]1CC[C@@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Reaction time: 6 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (50 mg), 4-dimethylamino-pyridine (DMAP, 1 mg) and triethylamine (30 μL) are dissolved in tetrahydrofurane (1 mL), treated with isocyanatoethane (11 μL) and stirred for 6 hours. Triethylamine (60 μL) and isocyanatoethane (22 μL) are added and the mixture is stirred for 12 hours at 70° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is used directly in the next step. LC (method 4): tR=1.20 min; Mass spectrum (ESI+): m/z=787 [M+H]+.
Reaction SMILES: O[CH:2]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH:26][C:27](=[O:32])C(C)(C)C)[CH:3]([CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)C(OC)=O.O.Cl>CO>[NH:11]1[CH2:10][CH2:9][CH:8]([C:3]2[C:27](=[O:32])[NH:26][C:25]3[CH:24]=[CH:23][S:22][C:21]=3[CH:2]=2)[CH2:13][CH2:12]1
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1sccc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]c2ccsc2cc1C1CCNCC1
Yield: 97 %

Procedure:
Tert-butyl 4-(1-hydroxy-3-methoxy-3-oxo-1-(3-pivalamidothiophen-2-yl)propan-2-yl)piperidine-1-carboxylate (10 g, 21.34 mmol) was dissolved in MeOH (20 mL), water (20.00 ml), hydrochloric acid (concentrated, 20 ml, 244 mmol), the resulting red pink solution was heated, the color changed to dark tan, and the mixture was refluxed in a oil bath under N2 over night, conversion was completed as determined by LC/MS. Most of the solvent was removed on rotary vacuo, the resulting gum type residue was triturate with EtOAc/MeOH (10 mL/2 mL), filtered and washed with EtOAC/MeOH (10 mL/1 mL) to afford the expected product, 6-(piperidin-4-yl)thieno[3,2-b]pyridin-5(4H)-one (4.85 g, 97%), as a brown solid. 1H-NMR (400 MHz, MeOD) δ ppm 1.83-1.94 (m, J=13.41, 13.13, 13.13, 3.90 Hz, 2 H) 2.13 (d, J=13.85 Hz, 2 H) 3.08-3.19 (m, 4 H) 3.50 (dd, J=10.58, 2.01 Hz, 2 H) 7.08 (d, J=6.04 Hz, 1 H) 7.78 (d, J=5.54 Hz, 1 H) 7.96 (s, 1 H); Mass spec. 235.16 (MH+), Calc. for C12H14N2OS 234.08.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[O:11]1[C:15]2[CH:16]=[CH:17]C=CC=2N=C1>>[O:11]1[CH2:15][CH:16]1[CH2:17][O:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc2ocnc2c1
Reactant: Oc1nc2ccccc2s1
Product: c1ccc2sc(OCC3CO3)nc2c1

Procedure:
Compound 44 was prepared in the manner of compound 6 substituting 2-hydroxy-benzothiazole for compound 8 in partC-5 of Example 1.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:14]([C:15]([NH:17][C:18]3([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)[CH2:20][CH2:19]3)=[O:16])[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH2:9]2)=[CH:5][CH:4]=1.O[Li].O>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:14]([C:15]([NH:17][C:18]3([C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)=[O:16])[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH2:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Yield: 93 %

Procedure:
The title compound (E22) (65 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4-carboxamido)cyclopropyl)benzoate (D140a) (72 mg). (LiOH H2O: 4 eq; reaction time: 10 hrs)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[C:11](O)(=[O:13])C.C1N2CN3CN(C2)CN1C3>O>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH:11]=[O:13])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2n1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2nc(Cl)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
6-Chloro-1H-pyrrolo[2,3-b]pyridine (0.041 g, 0.27 mmol) was successively added with acetic acid (0.1 mL), water (0.2 mL), and hexamethylenetetramine (0.053 g, 0.28 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was added with water, and the precipitated solid was collected by filtration to obtain 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.031 g, 64%).
Reaction SMILES: [O-]CC.[Na+].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.C(O)(=O)C>C(O)C>[CH2:15]([O:14][C:12]([C:11]1[CH:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20](=[O:19])[N:5]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2)=[O:13])[CH3:16]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)Cc1ccccn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C(=O)OCC)c2ccccn2c1=O
Reaction time: 1 h

Procedure:
To a solution of sodium ethoxide (sodium, 151 mg) in ethanol (20 ml) was added ethyl pyrid-2-ylacetate (1 ml) at room temperature and the mixture was stirred for 1 hour at the same temperature. To the mixture was added diethyl ethoxymethylenemalonate (1.33 ml) at room temperature and the mixture was stirred at room temperature overnight. To the mixture was added acetic acid (0.75 ml) at room temperature and the precipitate was filtered and washed with water to give 1,3-diethoxycarbonyl-4H-quinolizin-4-one (896 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:6]2[C:5]3[CH2:9][CH2:10][CH2:11][C:4]=3[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc3c2CCC3)CC1
Temperature: 60 °C
Yield: 46.2 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (2.71 g, 14.34 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.45 g, 17.20 mmol, 1.2 equiv) in anhydrous DMF (40 mL) was heated to 60° C. for 18 h. The organic phase was concentrated under reduced pressure and the crude reaction mixture extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4 and the product purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (14:3→1:1) providing 2.34 g (47%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.32-1.43 (m, 2H), 1.39 (s, 9H), 1.79-1.82 (m, 2H), 2.0 (quint, J=7.5 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.80-2.88 (m, 2H), 3.93-3.98 (m, 2H), 4.04-4.13 (m, 1H), 7.07 (d, J=8.0 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 21.12, 26.42, 28.04, 31.17, 33.19, 42.55, 47.12, 78.53, 114.87, 153.84, 157.95, 159.02, 172.18. MS (ISP): 353.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:19]#[C:18][C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[CH:28][CH:29]=1
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.096 g, 0.38 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.094 g, 0.34 mmol), triethyl amine (3 mL), tetrahydrofuiran (3 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) the title compound was obtained (0.137 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.47 (d, 2H, J=7.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 7.24 (d, 2H, J=7.9 Hz), 6.82 (d, 1H, J=2.1 Hz), 3.70 (s, 3H), 3.63 (s, 2H), 2.22-2.13 (m, 1H), 1.85 (s, 2H), 1.38 (s, 6H), 1.36 (s, 6H), 0.94-0.86 (m, 2H), 0.68-0.63 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NCc1ccccn1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCc1ccccn1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-(aminomethyl)pyridine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-2-ylmethyl)terephthalamide. MS (Q1) 477 (M)+.