Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:17][OH:18])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[CH:36][O:35][N:34]=2)=[CH:29][CH:28]=1.O1C=NC(C2C=CC(CN([C@@H]3CCCC[C@H]3CO)S(C3C=CC(Cl)=CC=3)(=O)=O)=CC=2)=N1>>[O:35]1[CH:36]=[N:37][C:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][N:10]([C@@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[CH2:17][OH:18])[S:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:8])=[CH:28][CH:29]=2)=[N:34]1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)s1
Reactant: BrCc1ccc(-c2ncon2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)s1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Yield: 13.4 %

Procedure:
The title compound was synthesized from 5-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (100 mg, 0.32 mmol), cesium carbonate (126 mg, 0.39 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (93 mg, 0.39 mmol) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-5-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (20 mg, 13%), 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (s, 1H), 8.07 (m, J=8.31 Hz, 2H), 7.54 (m, J=8.31 Hz, 2H), 7.30 (d, J=4.03 Hz, 1H), 6.91 (d, J=4.03 Hz, 1H), 4.72 (d, J=15.36 Hz, 1H), 4.16 (d, J=15.36 Hz, 1H), 3.60-3.65 (m, 1H), 3.68 (dd, J=11.96, 2.90 Hz, 1H), 3.09 (d, J=12.09 Hz, 1H), 1.70-1.80 (m, 1H), 1.66 (d, J=12.84 Hz, 1H), 1.36-1.61 (m, 4H), 1.12-1.28 (m, 1H), 0.92-1.09 (m, 2H). Analytical HPLC R.T.=21.54 min. MS [M+H]+=468. HRMS [M+H]+ calc'd 468.0819, found 468.0815.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][NH:13][C:12]1[CH:14]=[CH:15][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:7]
Reactant: CCOC(=O)C=O
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CNc1ccc(F)cc1
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A solution of ethyl glyoxylate (2.47 g, 0.024 mol) in 1,2-dichloroethane (30 mL) under argon at room temperature was treated succesively with 4-fluoroaniline (1.80 g, 0.016 mol), sodium triacetoxyborohydride (5.12 g, 0.024 mol) and acetic acid (1 mL). After stirring for two hours, the mixture was concentrated, dissolved in ethyl acetate and washed 5% sodium bicarbonate, water and brine. The dried (anhydrous magnesium sulfate) organic solution was concentrated and crystallized from ether/hexanes to give the title product (2.07 g, 65%) as a colorless solid, mp 72°-73° C. Analysis calculated for C10H12 FNO2 ·0.07 H2O: C, 60.54; H, 6.16; N, 7.06; F, 9.58. Found: C, 60.75; H, 6.15; N, 6.96; F, 9.13.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O)(C)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Fc1cccc2c(N3CCSCC3)nc(Cl)cc12
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CC(C)O
Product: Fc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 90 %

Procedure:
1-Thiomorpholino-3-piperazino-5-fluoro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3-chloro-5-fluoro-isoquinoline by heating for 30 hours with piperazine in diphenyl ether at 200°C. M.p. 213°-215°C (from isopropanol); yield: 90% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25](O)=[O:26])[CH:19]=3)[NH:14]2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH:28]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29]1>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([NH:34][S:31]([CH:28]4[CH2:30][CH2:29]4)(=[O:33])=[O:32])=[O:26])[CH:19]=3)[NH:14]2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCCC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cc(F)cc(N2CCCC2)c1
Temperature: 60 °C
Yield: 19.7 %

Procedure:
A mixture of 2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 0.14 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol), 4-dimethylaminopyridine (24.4 mg, 0.20 mmol), cyclopropanesulfonic acid amide (51 mg, 0.42 mmol) in dichloromethane (3 mL) was heated for 12 hours at 60° C. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (13 mg, 20%) as a light yellow solid: LC/MS m/e calcd for C25H30FN3O3S (M+H)+: 472.6, observed: 472.2.
Reaction SMILES: [CH3:1]/[C:2](/[C:9]1[S:10][C:11]([CH2:14][CH:15](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:16])=[CH:12][CH:13]=1)=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O>[N:28]([CH:15]([CH3:16])[CH2:14][C:11]1[S:10][C:9](/[C:2](/[CH3:1])=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:13][CH:12]=1)=[N+:29]=[N-:30]
Reactant: CCOC(=O)/C=C(\C)c1ccc(CC(C)OS(=O)(=O)c2ccc(C)cc2)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)/C=C(\C)c1ccc(CC(C)N=[N+]=[N-])s1

Procedure:
5-[(RS)-2-hydroxyprpyl]-2-thienyl methyl ketone and triethyl phosphonoacetate were reacted in alcohol in the presence of sodium ethylate to give ethyl (E)-5-[(RS)-2-hydroxypropyl]-β-methyl-2-thiopheneacrylate. With p-toluenesulphochloride there was obtained therefrom ethyl (E)-β-methyl-5-[(RS)-2-[(p-toluenesulphonyl)oxy]propyl]-2-thiopheneacrylate (melting point 121°, from methylene chloride/alcohol). Reaction of this ester with sodium azide in dimethyl sulphoxide gave ethyl (E)-5-[(RS)-2-azidopropyl]-β-methyl-2-thiopheneacrylate. Reduction of the latter ester with triphenylphosphine and hydrolysis led to ethyl (E)-5-[(RS)-2-aminopropyl]-β-methyl-2-thiopheneacrylate; ε320 =17970.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[C:33](O)=[O:34]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CCCO1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CCCO1

Procedure:
The title compound, white solid (100 mg, 78%), MS (ISP) m/z=429.3 [(M+H)+], mp 176.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and rac-tetrahydrofuran-2-carboxylic acid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[N:30]=[N:31][N:32]([CH2:34][CH3:35])[N:33]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:22][CH2:23][N:24]([C:55]([C:54]6[CH:58]=[CH:59][C:51]([C:45]7[C:46]8[CH:47]=[C:48]([O:49][CH3:50])[C:39]([O:38][CH2:36][CH3:37])=[CH:40][C:41]=8[C@H:42]8[CH2:63][S:62][CH2:61][CH2:60][C@H:43]8[N:44]=7)=[CH:52][CH:53]=6)=[O:56])[CH2:25][CH2:26]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[N:30]=[N:31][N:32]([CH2:34][CH3:35])[N:33]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc7c(c6)OCO7)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(1,3-benzodioxol-5-yl)-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (94 mg; compound B77) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (72 mg; compound C10) and HBTU (151 mg) in DCM/DMF (15 ml/1 ml) in the presence of DIPEA (188 mg) according to the procedure described in example 2 to afford the title compound after purification by two-time flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 65/30/5 to 30/60/10 to 0/90/10 (v/v/v)].
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][NH:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=2>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:16][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C(=O)NNc1nc2ccc([N+](=O)[O-])cc2nc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nnc2c(Cl)nc3cc([N+](=O)[O-])ccc3n12
Temperature: 50 °C
Yield: 89.6 %

Procedure:
A mixture of 2.0 g (~5.9 mmol) of 3-chloro-2-(2-ethoxalylhydrazino)-6-nitroquinoxaline and 20 ml of phosphorus oxychloride was refluxed for 90 min. After cooling to 50° C. the reaction mixture was poured into ice-water to give 1.7 g (~90%) of the title compound as a precipitate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH2:21][NH:22][CH:23]1[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]1.[Cl:38][C:39]1[C:40]2[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=2[S:42][C:43]=1[C:44](Cl)=[O:45]>>[Cl:38][C:39]1[C:40]2[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=2[S:42][C:43]=1[C:44]([N:22]([CH2:21][C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:23]1[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:25][CH2:24]1)=[O:45]
Reactant: COc1ccc(-c2ccc(C(=O)C(F)(F)F)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccc(C(=O)C(F)(F)F)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 16 (467 mg, 0.90 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (290 mg, 1.26 mmol) using Method D to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Br:11])[CH:3]=1.[OH-].[K+].CN(C)[C:16](=[O:20])N(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[C:6]([O:20][CH2:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1
Reactant: CN(C)C(=O)N(C)C
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: Brc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
(According to Effenberger, Chem. Ber. 163 (1991).) 1,3-dibromo-5-nitrobenzene (2.81 g, 10.0 mmol), freshly powdered potassium hydroxide (1.00 g, 17.8 mmol) and tetrabutylammonium bromide (0.32 g, 1.00 mmol) were dissolved in tetramethyl urea (TMU, 8 mL). Oxygen was bubbled through the reaction mixture for 5 min and a solution of benzyl alcohol (1.30 g) in TMU (2 mL) was added drop-wise at room temperature over a period of 1 h. The mixture was stirred for 6 h at room temperature during which oxygen was bubbled through. The reaction mixture was poured on ice (30 g) and was extracted with tert-butylmethyl ether (2×50 mL). The combined organics were dried (MgSO4) and concentrated to give the crude product which was purified by FC (120 g SiO2, AcOEt/heptane 1:4) to provide 3.15 g (92%) of 3,5-dibromo-1-benzyloxybenzene.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:28])([CH:25]([CH3:27])[CH3:26])[CH3:24])=[CH:19][CH:18]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:28])([CH:25]([CH3:26])[CH3:27])[CH3:24])=[CH:21][CH:22]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(C)(O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Yield: 61.3 %

Procedure:
A mixture of 2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-3-methyl-butan-2-ol (50 mg, 0.13 mmol) and 10% palladium on activated carbon (15 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-phenyl}-3-methyl-butan-2-ol (30 mg, 60%): LC/MS m/e calcd for C25H32N2O [M+H]+ 377.55, observed 377.2; 1H NMR (400 MHz, CD3OD) δ ppm 0.80 (d, J=6.82 Hz, 4H) 0.86 (d, J=6.82 Hz, 4H) 1.20-1.31 (m, 1H) 1.46-1.53 (m, 5H) 1.59-1.77 (m, 3H) 1.97 (t, J=6.82 Hz, 1H) 2.05-2.13 (m, 1H) 2.19-2.26 (m, 1H) 4.17 (t, J=7.96 Hz, 1H) 6.33 (s, 1H) 7.04 (dd, J=7.71, 4.93 Hz, 1H) 7.28 (m, J=8.34 Hz, 2H) 7.38 (m, J=8.08 Hz, 2H) 7.89 (dd, J=7.83, 1.26 Hz, 1H) 8.06 (d, J=3.79 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[C:4]3[C:11]4([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]4)[CH2:10][CH:9]([CH:18]4[CH2:23][CH2:22][CH2:21][O:20][CH2:19]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: CN1OC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(C3CCCOC3)Oc3ccc(-c4cc(F)cc(F)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 30.1 %

Procedure:
In a 10 mL flask, 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (30 mg, 0.08 mmol), Pd(PPh3)2Cl2 (15 mg), 3,5-difluorophenylboronic acid (25 mg, 0.16 mg) were dissolved in 1,4-dioxane (4.0 mL), followed by addition of Cs2CO3 (2 N, 1 mL). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give 6-(3,5-difluorophenyl)-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (10 mg, 30%). 1H-NMR (MeOD): 1.62 (m, 2H), 1.96 (m, 3H), 2.70 (m, 1H), 3.30 (s, 3H), 3.38 (m, 4H), 3.83 (m, 2H), 4.12 (m, 2H), 6.84 (m, 1H), 6.96 (m, 1H), 7.18 (m, 2H), 7.64 (m, 1H), 7.86 (d, 1H).
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([CH2:16][C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([CH2:16][C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[C:18]=2[S:6]([Cl:10])(=[O:8])=[O:7])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Clc1ccc(Cc2cc3ccccc3s2)cc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1c(Cc2ccc(Cl)cc2)sc2ccccc12

Procedure:
2-(4-chlorobenzyl)benzo[b]thiophene-3-sulfonylchloride was prepared by the method of Example 40B with DMF (70 mmoles, 5.4 ml), sulfurylchloride (2.3 mmoles, 1.9 ml) and 2-(4-chlorobenzyl)-benzo[b]thiophene (4.6 mmoles, 1.2 g). Flash chromatography (2% ethyl acetate/hexanes) provided 0.51 g (31%) of an orange-yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=3[CH:25]([CH3:27])[CH3:26])=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].S(OC)(O[CH3:34])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[CH:25]([C:16]1[CH:17]=[C:18]([C:21]([F:23])([F:22])[F:24])[CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][N:1]2[CH3:34])=[O:12])([CH3:27])[CH3:26]
Reactant: CC(C)c1cc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2[nH]ncc12
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2c1cnn2C
Reaction time: 1.5 h

Procedure:
To a solution of Example 4C (0.468 g, 2.2 mmol) in DMF (6 mL) was added NaH (0.104 g, 2.6 mmol) and the mixture was stirred for 90 minutes. Dimethyl sulfate (Me2SO4, 0.22 mL, 2.3 mmol) was added, and the mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (1200 mL), washed sequentially with H2O (400 mL) and brine (400 mL), dried (Na2SO4), filtered, concentrated under reduced pressure, and purified by chromatography (75% diethyl ether/Hexanes to 100% diethyl ether) to provide the title compound. 1H-NMR (DMSO-d6) δ 8.81 (s, 1H), 8.04 (s, 1H), 7.64 (d, 1H), 7.60 (s, 1H), 7.55 (m, 2H), 7.25 (t, 1H), 7.14 (d, 1H), 6.81 (t, 1H), 4.49 (d, 2H), 3.99 (s, 3H), 3.30 (m, 1H), 1.25 (d, 6H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:4]1)[CH3:2].FC1C=C(C=CC=1)C[C@H]1CCNC1>>[CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@@H](Cc2cccc(F)c2)C1
Agent: Fc1cccc(C[C@H]2CCNC2)c1
Product: CCN1CC[C@H](Cc2cccc(F)c2)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 97 starting with 3-(S)-(3-fluoro-benzyl)pyrrolidine (Intermediate 116).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:22]=[C:21]([O:29][C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)[CH:20]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH3:40][C:38]1[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=[C:30]([O:29][C:21]2[N:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:39]=1
Reactant: Cc1cc(Oc2cc(Cl)nc(C(F)(F)F)n2)cc2oc(=O)[nH]c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)nc(C(F)(F)F)n2)cc2oc(=O)[nH]c12
Reaction time: 0.5 h

Procedure:
90 mg (0.35 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 125 mg (0.36 mmol) 6-(6-chloro-2-trifluoromethyl-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.20 mL (1.16 mmol) DIPEA in 2.0 mL NMP were stirred for 14 h at 60° C. After cooling the reaction mixture was mixed with water and stirred for 30 min. The precipitate formed was suction filtered and dried.
Reaction SMILES: C([C:3]([CH2:36][CH3:37])(P([O-])([O-])=O)[C:4]1C=[CH:15][C:14]2[C:13]3[C:8](=[CH:9]C(C(CC)(CC)P([O-])([O-])=O)=[CH:11][CH:12]=3)[C:7]([CH2:29][CH2:30][CH3:31])(CCC)[C:6]=2[CH:5]=1)C.C1OC2C=CC(C=O)=CC=2O1.[OH-].[K+]>C1COCC1.CS(C)=O.C(O)C>[CH:36]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:29](=[CH:30][CH:31]=[CH:9][CH:8]=3)[CH2:15][C:14]=2[C:13]=1[CH:12]=[CH2:11])=[CH2:37]
Reactant: CCCC1(CCC)c2cc(C(CC)(CC)P(=O)([O-])[O-])ccc2-c2ccc(C(CC)(CC)P(=O)([O-])[O-])cc21
Agent: O=Cc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CS(C)=O
Product: C=Cc1ccc2c(c1C=C)Cc1ccccc1-2
Temperature: 70 °C
Yield: 178.7 %

Procedure:
A suspension of 2,7-bis(diethylphosphonatomethyl)-9,9-dipropylfluorene (4) (2.70 g, 5 mmol), 3,4-methylenedioxybenzaldehyde (7) (1.60 g, 11 mmol) and potassium hydroxide (0.85 g, 15 mmol) in THF (30 mL) and DMSO (1 mL) was heated at 70° C. for 7 hours. The suspension was diluted with Ethanol (50 mL) and the solvent removed under vacuum. The product was purified by refluxing in Methanol followed by filtration. After drying, (II-5) was obtained as a pale yellow powder (1.95 g, 72%). The UV/VIS spectrum of (II-5) in methyl ethyl ketone (MEK) has two maxima at 382 nm and at 401 nm with a molar extinction coefficient of 79099 Mol−1 cm−1 and 63911 Mol−1 cm−1 respectively. Under UV irradiation (II-5) shows a strong blue fluorescence. The 1H-NMR data in CDCl3 are summarized in table 3.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:18])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.C(OCC)(=O)C>O>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:18])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)c(-c3ccccc3)[nH]c2c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(-c2ccccc2)[nH]c2cc(O)ccc12
Temperature: 25 °C

Procedure:
6-Methoxy-3-methyl-2-phenyl-1H-indole (5.00 g; synthesized according to the process described in Tetrahedron, vol. 41, p. 4615 (1985)) and pyridine hydrochloride (11.56 g) were stirred at 180° C. for 100 minutes. After the reaction mixture was cooled down to room temperature, ethyl acetate and water were added. After the layers were separated, the organic layer was washed sequentially with aqueous 0.5 N hydrochloric acid and saturated brine, and dried. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography to yield the title compound (4.50 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][C:12]([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])=[CH:13][CH:14]=2)[N:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.CCOCC>[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][C:12]([CH:18]([CH2:24][OH:25])[CH2:19][OH:20])=[CH:13][CH:14]=2)[N:9]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2ccc(C)nc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2ccc(C(CO)CO)cc2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a solution of 1.0 N LAH (15.3 mL, 15.3 mmol) in THF was added diethyl 2-(2-methylquinolin-7-yl)malonate (1.15 g, 3.82 mmol) in Ether (30 mL) slowly at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. Sodium sulfate decahydrate (2.0 g) was added and stirred at ambient temperature for 30 minutes. The solid was removed by filtration and washed with ethyl acetate (50 mL). The filtrate was concentrated and the residue obtained was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 40M column, 0-70% CH3CN/water gradient; 30 CV) to give 2-(2-methylquinolin-7-yl)propane-1,3-diol (0.34 g, 1.56 mmol, 41.0% yield) as a solid.