Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][CH2:31]O)=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:58]([O:62][C:63]([NH:65][C:66]([NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])=[NH:67])=[O:64])([CH3:61])([CH3:60])[CH3:59].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[C:72]([O:71][C:69](=[O:70])[N:68]=[C:66]([NH:65][C:63]([O:62][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:64])[NH:67][CH2:31][CH2:30][O:29][C:28]1[CH:33]=[C:34]([F:35])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:26]([F:36])[CH:27]=1)([CH3:75])([CH3:74])[CH3:73]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 8 h
Yield: 128.5 %

Procedure:
To a solution of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanol (153 mg, 0.27 mmol) in THF (0.39 mL) were added PPh3 (107 mg, 0.41 mmol), 1,3-bis(tert-butoxycarbonyl)guanidine (144 mg, 0.55 mmol) and DIAD (85 μL, 0.41 mmol). After stirring overnight, the reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography (80% EtOAc/hexanes) to afford tert-butyl(tert-butoxycarbonylamino)(2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethylamino)methylenecarbamate (279 mg), which was taken to the final step without further purification. MS (EI) m/z 804.5 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10]C)(=O)[CH2:2][C:3]([O:5]CC)=O.[CH3:12][O:13]CCBr.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>>[OH:5][CH:3]([CH2:2][CH2:1][O:9][CH3:10])[C:12]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1)=[O:13]
Reactant: Cc1ccc(N)nc1
Reactant: COCCBr
Reactant: CCOC(=O)CC(=O)OCC
Product: COCCC(O)C(=O)Nc1ccc(C)cn1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A16 and Intermediate A2 (Step 2-Step 3) starting from diethyl malonate, 2-bromoethyl methyl ether and 2-amino-5-picoline, 1H NMR (300 MHz, CDCl3) δ 9.24 (br s, 1H), 8.14 (m, 2H), 7.52 (dd, 1H), 4.48 (br s, 1H), 4.39 (m, 1H), 3.69 (m, 2H), 3.39 (s, 3H), 2.25 (m, 4H), 2.09 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1([CH2:9][CH2:10][CH:11]=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2].[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:24][OH:25]>>[CH3:24][O:25][CH:11]([O:12][CH3:13])[CH2:10][CH2:9][C:4]1([N+:1]([O-:3])=[O:2])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=CCCC1([N+](=O)[O-])CCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CO
Product: COC(CCC1([N+](=O)[O-])CCCC1)OC

Procedure:
Condense nitrocyclopentane (prepared from bromocyclopentane and sodium nitrite) and acrolein in tetrahydrofuran in the presence of sodium hydride to obtain 3-(1-nitrocyclopentyl)propionaldehyde. Treat this aldehyde with p-toluenesulfonic acid in methanol and isolate 3-(1-nitrocylopentyl) propionaldehyde dimethyl acetal. Hydrogenate this compound with Raney nickel. Isolate 3-(1-aminocyclopentyl)propionaldehyde dimethylacetal and dissolve in aqueous acetone in the presence of p-toluenesulfonic acid and heat under reflux, followed by addition of toluene and azeotrope the mixture to give 1-azaspiro[4.4]-Δ1 -nonane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.C1C(=O)N([Br:29])C(=O)C1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:29])=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCc2cccnc21
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCc2cc(Br)cnc21
Yield: 97.7 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (1.37 g, 5.85 mmole) in. CH2Cl2 (30 μL) was added glacial HOAc (3.4 mL, 58.5 mmole) and NBS (1.09 g, 6.14 mmole). After 72 hr the mixture was washed with 2.0 M NaOH, H2O. and brine. The mixture was dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (1.79 g, 98%) which was sufficiently pure for use in the next step: 1H NMR (400 MHz, CDCl3) δ 8.35 (s,1H), 7.51 (s, 1 H), 3.77 (m, 2 H), 2.75 (t,J=6.5 Hz, 2 H), 1.93 (m, 2 H), 1.54 (s, 9 H).
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5].[CH3:19][O:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1>>[NH2:1][C:2]1[N:17]=[CH:16][C:15]([C:26]2[CH:25]=[N:24][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH:27]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5]
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cnccc1NC(=O)c1cc(Br)cnc1N
Product: COCCn1cc(-c2cnc(N)c(C(=O)Nc3ccncc3C)c2)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-(3-methyl-pyridin-4-yl)-nicotinamide with 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole gives the compound “A22”; HPLC/MS: 1.07 min, [M+H]=353;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:17])[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>O1CCOCC1.C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:38])[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:17])[CH2:11]1
Reactant: O=C1CC(c2ccc(CO)cc2Br)S(=O)(=O)N1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C1CC(c2ccc(CBr)cc2Br)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[2-bromo-4-(hydroxymethyl)phenyl]isothiazolidin-3-one 1,1-dioxide (54.0 mg, 0.169 mmol) in 1,4-dioxane (5 mL) was added triphenylphosphine (49 mg, 0.18 mmol) and carbon tetrabromide (62 mg, 0.18 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with acetonitrile and purified by preparative LCMS to give the product as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:5])[CH3:4].C(N(CC)CC)C.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([F:30])[C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[N:20]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH:19]=[C:18]([C:38]([OH:40])=[O:39])[C:17]2=[O:41]>CN(C)C=O>[ClH:1].[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([F:30])[C:23]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3](=[O:5])[CH3:4])[CH2:26][CH2:25]1)[N:20]([C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[CH:19]=[C:18]([C:38]([OH:40])=[O:39])[C:17]2=[O:41]
Reactant: CC(=O)CCl
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)CC1
Product: Cl
Temperature: 80 °C

Procedure:
0.7 g of chloroacetone and 1.05 g of triethylamine are added to 2 g of 6,8-difluoro-1,4-dihydro-4-oxo-1-(4-fluorophenyl)-7-(1-piperazinyl)-quinoline-3-carboxylic acid in 25 ml of dimethylformamide and the mixture is heated at 80° C. for 3 hours. The suspension is concentrated in vacuo and the residue is stirred with water, filtered off with suction and dried. The product is heated in 15 ml of dilute hydrochloric acid (1:1), precipitated with 30 ml of ethanol, filtered off with suction and dried.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14].C(OCC)C>C(OCC)C.C1COCC1>[OH:3][C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([CH3:2])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: CC(=O)c1ccc(C#N)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)CC(C)(O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Dissolve 4-acetylbenzonitrile (1 g, 6.88 mmol) in diethyl ether/THF (1:1, 60 mL) and cool the solution to 0° C. Add 1 M neopentylmagnesium chloride in diethyl ether (8.3 mL, 8.3 mmol) under nitrogen and stir the mixture at room temperature overnight. Add saturated aqueous NH4Cl and extract the mixture twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1, 9:1) to give the desired intermediate (364 mg, 24%).
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.C(C1CC=CCCC=CCC(C(C)C)N=N1)(C)C.[CH:37]1([CH:43]2[CH2:54][CH:53]=[CH:52][CH2:51][CH2:50][CH:49]=[CH:48][CH2:47][CH:46]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)[N:45]=[N:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[NH2:44][CH:43]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]([NH2:45])[CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: C1=CCC(C2CCCCC2)N=NC(C2CCCCC2)CC=CCC1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Agent: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Product: NC(CCCCCCCCC(N)C1CCCCC1)C1CCCCC1
Yield: 90.3 %

Procedure:
If there are used in the manner described under (a), instead of 250 g (1 mol) of 3,12-diisopropyl-1,2-diaza-1,5,9-cyclododecatriene, 328.5 g (1 mol) of 3,12-dicyclohexyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with otherwise the same procedure, there is obtained, as the main fraction, 304 g (90% of theory) of 1,10-diamino-1,10-dicyclohexyldecane in the form of colourless oil [b.p. 190°-193° C./0.05 Torr; nD20 =1.4944; IR (liquid) inter alia bands at 3355, 3278 and 1613 cm-1 ].
Reaction SMILES: CO[C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[C:17]([F:20])([F:19])[O:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4].[NH3:25]>CO>[F:20][C:17]1([F:19])[C:16](=[O:21])[N:15]([CH3:22])[C:14]2[CH:23]=[CH:24][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:25])=[O:4])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18]1
Reactant: N
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)OC(F)(F)C(=O)N3C)C(=O)O1
Solvent: CO
Product: CN1C(=O)C(F)(F)Oc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reaction time: 16 h
Yield: 44 %

Procedure:
To a stirred solution of (5R)-3-(2,2-difluoro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (Step 3, 50 mg, 0.14 mmol) in MeOH (1 mL) is added 2M NH3 in MeOH (2 mL, 4 mmol). The resulting mixture is stirred for 16 h at which time the reaction is concentrated under reduced pressure and purified by silica gel chromatography (EtOAc) to give the title compound as a light yellow solid (21 mg, 44%), 1H NMR (300 MHz, DMSO) δ 7.86 (br s, 1H), 7.61 (d, 2H), 7.52-7.41 (m, 2H), 5.02 (dd, 1H), 4.28 (t, 1H), 4.02 (dd, 1H), 3.42 (s, 3H); MS for C13H11F2N3O5 m/z 328.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[C:3]=1[C:10](Cl)=[O:11].C(=O)([O-])[O-:14].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[C:3]=1[C:10]([OH:11])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1c(Cl)nc(Cl)nc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1c(Cl)nc(Cl)nc1Cl

Procedure:
A solution of 12.35 parts of trichloropyrimidine-5-carbonyl chloride in 200 parts by volume of acetone is stirred into a suspension of 12.12 parts of γ-(β-sulfatoethylsulfonyl)-propylamine in 250 parts by volume of acetone at 0° C. The reaction is carried out at 5° to 10° C., while maintaining a pH of 6.5 by means of 15% strength aqueous sodium carbonate solution. The trichloro-pyrimidine-5-carboxylic acid compound thus obtained of the formula ##STR25## is isolated by evaporation of the solution under reduced pressure. The compound is a solid substance; it is characterized by the following 13C-NMR spectroscopy values in hexadeutero-dimethyl sulfoxide: δ (in ppm)=21.7; 37.9; 51.2; 52.3; 60.0; 129.4; 157.5; 159.4; 160.6 compared with tetramethylsilane as the internal standard.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([O:10]CC)=O)=[N:3]1.[CH3:13][Si](Cl)(C)C.C[Li]>O1CCCC1>[C:8]([C:4]1[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=1)(=[O:10])[CH3:13]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)c1cc(C)n(C)n1
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1cc(C)n(C)n1
Temperature: -100 °C
Reaction time: 0.08 h

Procedure:
Ethyl 1,5-dimethylpyrazole-3-carboxylate (3.59 g, 21.4 mM) was dissolved in dry tetrahydrofuran (70 ml) and cooled to −100° C. whilst under an atmosphere of argon. Trimethylsilylchloride (13.5 ml, 107 mM) was added by rapid dropwise addition. Immediately after methyllithium (77.7 ml of 1.1M solution in diethylether, 85.5 mM) was added dropwise in such a way that the internal temperature never exceeded −85° C. After complete addition the heterogeneous reaction was allowed to warm to room temperature. Most of the solvent was removed by evaporation in vacuo before treating with ethanol (6 ml) followed by water (6 ml). After vigorously stirring for 5 minutes the mixture was diluted with ethyl acetate and water. The pH was adjusted to 7 by treating with saturated sodium bicarbonate solution. The organic phase was separated and washed with brine before drying (MgSO4). Purification was accomplished by chromatography on silica gel (12×4.25 cm) loading in dichloromethane and eluting with 40% ethylacetate in hexane followed by 60% ethyl acetate in hexane. Removal of the solvents gave the title compound as a coloured oil which solidified on standing at room temperature (1.42 g): υmax (CH2Cl2) 1679, 1551, 1448, and 1373 cm−1; δH (CDCl3) 2.30 (3H, s), 2.54 (3H, s), 3.84 (3H, s), 6.53 (1H, d, J 0.55 Hz); E.I. m/e 138 (95%), NH3DCI m/e 139 (100%).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O[C:13](=O)[C:14]([F:17])(F)F)=O.[C:21]1([CH3:27])[CH:26]=CC=[CH:23][CH:22]=1>>[F:17][C:14]1[CH:13]=[CH:26][C:21]([CH:27]=[C:2]2[CH2:3][CH2:4][CH2:5][NH:6][C:1]2=[O:7])=[CH:22][CH:23]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCCCN1
Reactant: Cc1ccccc1
Product: O=C1NCCCC1=Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
This example illustrates the preparation of the compound of formula II (n=2, R1=p-fluorophenyl) at a multi-kilogram scale. A 30 gallon (120 L) glass-lined reactor was charged with valerolactam (18.0 kg) and toluene (42.0 kg). Trifluoroacetic anhydride (42.0 kg) was added over 30 min and the mixture was stirred for an additional 60 min. Volatiles were distilled off at 60-70° C. at 140 torr. Toluene (50.0 kg) was added and the mixture was further distilled until approximately 27 L remained in the pot and this process was repeated twice. To the residue was added tert-butanol (18.8 kg) and 4-fluorobenzaldehyde (20.3 kg). The resultant solution was slowly transferred to 100 gallon (400 L) glass-lined reactor containing potassium tert-butoxide in tetrahydrofuran (122 kg of a 20% solution). The mixture was warmed to 60° C. for 1 h. Volatiles were distilled at 40-50° C. at 250 torr to a volume of approximately 100 L. Water (180 L) was added to the slurry at 40° C. and the mixture was cooled to 5° C. for 2 h and collected by filtration. The wet cake was washed and reslurried with water (3×200 L) and dried in a tray dryer (50° C., 50 torr) to afford crude 3-p-fluorobenzylidene-2-piperidone (32.6 kg) whose purity by HPLC was 70.3 wt % (95.4 area %).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:31](Cl)(=[O:35])[C:32](Cl)=[O:33].[OH2:37]>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:23][CH:24]=4)=[CH:16][CH:17]=3)[C:12]([C:31](=[O:35])[C:32]([OH:37])=[O:33])=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O
Product: CC(C)(C)c1ccc(Cn2cc(C(=O)C(=O)O)c3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 1-[4-(tert-butyl)benzyl]-5-[4-(tert-butyl)phenyl]-1H-indole and oxalyl chloride in substantially the same manner, as described in Step 3 of Example 25. The product was obtained as a light brown solid, mp: 111-112° C. Mass spectrum (ESI, [M+H]+) m/z 468; 1HNMR (400 MHz, DMSO-d6): δ 13.50 (br s, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 7.68 (d, 1H, J=8.55 Hz), 7.58-7.54(m, 3H), 7.48 (d, 2H, J=8.40 Hz), 7.36 (d, 2H, J=8.25 Hz), 7.25 (d, 2H, J=8.40 Hz), 5.56 (s, 2H), 1.31 (s, 9H), and 1.22 ppm (s, 9H). Elemental Analysis for C31H33NO3.0.2 H2O: Calculated: C, 79.02; H, 7.14; N, 2.97. Found: C, 78.97; H, 7.22; N, 2.90.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[CH3:18][C:19]1[CH:24]=[C:23]([CH2:25]O)[CH:22]=[CH:21][N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:60]CCl>>[ClH:60].[CH3:18][C:19]1[CH:24]=[C:23]([CH2:25][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)[CH:22]=[CH:21][N:20]=1
Reactant: ClCCl
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Reactant: Cc1cc(CO)ccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(COc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)ccn1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (200 mg, 0.783 mmol, Description 3) and (2-methyl-4-pyridinyl)methanol (107 mg, 0.783 mmol) in dichloromethane (15 ml) was stirred under argon at room temperature, Triphenylphosphine (205 mg, 0.783 mmol) and diisopropyl azodicarboxylate (0.152 ml, 0.783 mmol) were then successively added. The resulting mixture was stirred at room temperature under argon for 16 hours. Solvent was removed by rotary evaporation and the desired product was purified by SCX eluting with 1M ammonia in methanol solution and high pH MDAP to give the title compound as a white solid. The free base solid was dissolved in methanol and treated with ethereal hydrochloride to give the desired compound as a hydrochloride salt (54 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:14](Br)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:14]([C:29]1[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Oc1c(Br)ccc2cc(OCc3ccccc3)ccc12
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Oc1c(-c2ccc(F)cc2)ccc2cc(OCc3ccccc3)ccc12
Temperature: 100 °C
Yield: 98 %

Procedure:
Combine methanesulfonic acid 6-benzyloxy-2-bromo-naphthalen-1-yl ester (10.0 g, 24.4 mmol), 4-fluorophenylboronic acid (10.2 g, 729 mmol), sodium carbonate (7.8 g, 73.6 mmol) and tetrakistriphenylphosphine palladium (2.8 g, 2.4 mmol) in a mixture of toluene (300 mL), ethanol (60 mL) and water (40 mL). Heat the mixture at 100° C. for 12 hours. Cool and filter the suspension through a pad of celite. Evaporate the solvent in vacuo. Wash the residue with sodium bicarbonate solution and brine. Dry with magnesium sulfate and concentrate in vacuo. Purify the residue over silica gel, eluting the material with a step gradient of methanol/dichloromethane (0 to 10%), to obtain 10.1 g (98%) of methanesulfonic acid 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yl ester.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=O.CCN(C(C)C)C(C)C.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26](=O)[O:25]C(=O)[CH2:23]2>C1COCC1.Cl>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:25])[O:5][C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:23]2
Reactant: O=C1Cc2cc(Br)ccc2C(=O)O1
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc2cc(Br)ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
N,N′-Carbonyldiimidazole (747 mg, 4.61 mmol, 1.50 equiv.) was added to a stirred mixture of ethyl hydrogen malonate (0.543 mL, 4.61 mmol, 1.50 equiv.) in THF (15 mL) and the mixture was stirred at room temperature. After 15 min, Hunig's base (1.072 mL, 6.14 mmol, 2.00 equiv.) was added followed by dropwise addition of 6-bromoisochroman-1,3-dione (740 mg, 3.07 mmol) in THF (10 mL). Upon completion, the reaction was diluted with 0.5 N HCl (10 mL), extracted with EtOAc (2×20 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-15% EtOAc/hexanes to give 683 mg of ethyl 2-(6-bromo-1-oxo-1H-isochromen-3-yl)acetate as a white solid.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:26]=[CH:25][C:14]2[CH:15]=[C:16]([CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20]3)[O:17][C:13]=2[CH:12]=1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CN(C=O)C>[CH:13]([OH:17])=[O:38].[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:26]=[CH:25][C:14]2[CH:15]=[C:16]([CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([NH:24][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:20]3)[O:17][C:13]=2[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN(Cc2cc3ccc(Oc4nc5ncccc5s4)cc3o2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCN(Cc2cc3ccc(Oc4nc5ncccc5s4)cc3o2)C1
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-ylmethyl]-pyrrolidin-3-ylamine (126 mg, 0.313 mmol) in DMF (2 mL) was added DIEA (125 μL, 0.938 mmol) followed by MsCl (72 μL, 0.938 mmol) and the resulting solution was stirred (rt, 1 h). The reaction mixture was filtered (Celite®) and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]1=[S:11]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(c2c(Cl)cccc2Cl)C1=S
Yield: 87.8 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 14.28 g of 2,6-dichlorophenyl-isothiocyanate, 10.75 g of sarcosine ethyl ester hydrochloride, 14.5 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether afforded the title compound (16.9 g) as a light peach solid, m.p. 207°-209° C. Anal. Calcd. for C10H8C12N2O S: C, 43.65; H, 2.93; N, 10.18. Found: C, 43.57; H, 2.61; N, 10.14. Mass spectrum (El, M.+) m/z 274.