Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C)C=O.[NH:19]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25](=[O:33])(=[O:32])[NH:24]2)[CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:19]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[S:25](=[O:33])(=[O:32])[NH:24]4)[CH2:20]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=S1(=O)NC2(CCNC2)c2ccccc21
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N1CCC2(C1)NS(=O)(=O)c1ccccc12)C1(c2ccc(Cl)cc2)CC1
Reaction time: 0.05 h

Procedure:
To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (40.0 mg, 0.000203 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) at 0 Celsius were added spiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxide (45.6 mg, 0.000203 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (99.0 mg, 0.000224 mol). The reaction mixture was stirred for 3 minutes, then N,N-Diisopropylethylamine (88.6 μL, 0.000508 mol) was added. The solution was then stirred at r.t. overnight. The crude material was purified by prep-HPLC to give the desired compound. MS (ESI): 404.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31]([NH:33][C:34]2([CH2:37]O)[CH2:36][CH2:35]2)=[O:32])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:59]>CCOCC>[Br:59][CH2:37][C:34]1([NH:33][C:31]([NH:30][C@@:15]([C:4]2[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:32])[CH2:36][CH2:35]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(NC1(CO)CC1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: O=C(NC1(CBr)CC1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reaction time: 14 h
Yield: 16.6 %

Procedure:
To a solution of (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(1-(hydroxymethyl)cyclopropyl)urea (Example 241, 43 mg, 0.08 mmol) in ether (0.4 mL) was added PPh3 (48 mg, 0.18 mmol) and CBr4 (58 mg, 0.18 mmol) at room temperature. The reaction mixture was stirred for 14 h and concentrated under reduced pressure and purified by ISCO chromatography (4 g column, eluting with 0-15% hexane/EtOAc over 14 min) to yield (R)-1-(1-(bromomethyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea as a white solid (8 mg, 17% yield). LCMS: RT=4.06 min [M+H] 601.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) ppm 0.82-1.03 (m, 4H), 3.47 (qt, J=12 Hz, 2H), 3.81 (ABqt, J=12 Hz, 2H), 5.01 (s, 1H), 5.39 (s, 1H), 5.86 (t, J=53 Hz, 1H), 6.61-6.78 (m, 2H), 6.80-7.25 (m, 10H).
Reaction SMILES: IC1C=CC(N2C3C=CC=C(O)C=3CC2)=CC=1.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH:32]=[CH:33][NH:34]2.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH:32]=[CH:33][N:34]2[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1cccc2[nH]ccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2c1CCN2c1ccc(I)cc1
Agent: [Cs+]
Product: COc1cccc2c1ccn2-c1ccc([N+](=O)[O-])cc1

Procedure:
The synthesis of 1-(4-iodophenyl)indolin-4-ol (92) is provided in Reaction Scheme 4b. The reaction of 1-fluoro-4-nitrobenzene and 4-methoxy-1H-indole in the presence of Cs2CO3 gave 4-methoxy-1-(4-nitrophenyl)-1H-indole (88), which was reduced with H2/Pd to yield 4-(4-methoxy-1H-indol-1-yl)benzenamine (89). The amino group of 89 was converted via the Sandmeyer reaction to 1-(4-iodophenyl)-4-methoxy-1H-indole (90) which on reduction with sodium borocyanohyride gave 1-(4-iodophenyl)-4-methoxyindoline (91). The indoline 91 was demethylated with BBr3 to provide the desired 92.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]([OH:11])=O)[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)[CH3:2].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[CH3:35][N:36]([C@H:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52][CH2:51]1)[C:37]([C:39]1[N:40]=[C:41]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[S:42][CH:43]=1)=[O:38].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]([N:47]2[CH2:48][CH2:49][CH:44]([C:41]3[S:42][CH:43]=[C:39]([C:37]([N:36]([CH3:35])[C@H:50]4[C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH2:53][CH2:52][CH2:51]4)=[O:38])[N:40]=3)[CH2:45][CH2:46]2)=[O:11])[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-ethyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (170 mg, 0.76 mmol) (i.e. the product of Example 16, Step C) in ethyl acetate (5.0 mL) was treated with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 1.0 mL, 1.6 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6 Step C) (219 mg, 0.56 mmol), triethylamine (0.5 mL, 3.75 mmol) in ethyl acetate (5 mL). The reaction mixture was then stirred at room temperature for 12 h. The resulting suspension was concentrated in vacuo and purified by silica gel MPLC using ethyl acetate/hexanes as eluant to give 200 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: [BH4-].[Na+].[N:3]([CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([Cl:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8])=[N+]=[N-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:55]=[CH:54][C:45]([CH2:46][CH:47]3[S:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])=[CH:44][CH:43]=2)[CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].C(O)(=O)C>[Cl:20][C:12]1[CH:11]=[CH:10][C:9]([C@@H:7]([OH:8])[CH2:6][NH:3][CH:36]2[CH2:41][CH2:40][N:39]([C:42]3[CH:55]=[CH:54][C:45]([CH2:46][CH:47]4[S:51][C:50](=[O:52])[NH:49][C:48]4=[O:53])=[CH:44][CH:43]=3)[CH2:38][CH2:37]2)=[CH:14][C:13]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CC4SC(=O)NC4=O)cc3)CC2)ccc1Cl
Reaction time: 2.5 h

Procedure:
To a stirred mixture of copper(ll) sulfate pentahydrate (0.042 g, 0.17 mmol) in N,N-dimethylformamide (15 mL) was added sodium borohydride (0.037 g, 1 mmol). To the resulting suspension was added N-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-chloro-phenyl]-methanesulfonamide (which was obtained in Example 25) (0.11 g, 0.38 mmol). After stirring for 20 minutes more copper(II) sulfate pentahydrate (0.042 g, 0.17 mmol) and sodium triacetoxyborohydride (0.064 g, 0.3 mmol) was added. The reaction mixture was stirred for 2.5 hours and then 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) (0.116 mg, 0.38 mmol), sodium triacetoxyborohydride (0.212 g, 1.0 mmol), and acetic acid (0.2 mL) were added. After stirring for 1.5 hours aqueous sodium bicarbonate solution was added and the resulting solid was collected. The product was purified by flash silica gel chromatography eluting with methylene chloride and methanol to give the title compound as a pale grey solid; mp >105° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.30-1.50 (m, 2H), 1.80-2.00 (m, 2H), 2.60-3.60 (m, 9H), 3.00 (s, 3H), 4.40-4.55 (m, 1H), 4.65-4.75 (m, 1H), 6.84 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.40-7.50 (m, 2H); MS (ES) m/z: 553.2 (MH+, 100%); HRMS Calcd. for C24H30ClN4O5S2 (MH+): 553.1440. Found: 553.1336.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:12][CH:13]=[C:5]([C:6]=23)[CH2:4][N:3]1[CH:14]1[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1.Cl>O1CCOCC1>[NH:16]1[CH2:17][CH2:18][CH2:19][CH:14]([N:3]2[CH2:4][C:5]3=[CH:13][NH:12][C:7]4[C:6]3=[C:11]([CH:10]=[CH:9][N:8]=4)[C:2]2=[O:1])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N2Cc3c[nH]c4nccc(c34)C2=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccnc3[nH]cc(c23)CN1C1CCCNC1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of tert-butyl 3-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate (10 mg, 0.028 mmol) in dioxane at 0° C. was added 4N HCl in dioxane (0.018 mL, 0.07 mmol) and the reaction mixture was stirred for 1 h to give a solid. The solid was filtered and dried to afford the title compound (5.6 mg) as its HCl salt. 1H NMR (400 MHz, CD3OD) δ 1.82-2.13 (m, 2 H) 2.13-2.31 (m, 2 H) 3.02 (td, J=13.07, 2.91 Hz, 1 H) 3.41 (d, J=1.77 Hz, 1 H) 3.44-3.51 (m, 2 H) 4.68-4.84 (m, 1 H) 5.00-5.19 (m, 2 H) 7.59 (s, 1 H) 7.73 (d, J=6.06 Hz, 1 H) 8.52 (d, J=6.06 Hz, 1 H)). [M+H] found 257.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:7]([C:12]([O:14]C)=[O:13])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:7]([C:12]([OH:14])=[O:13])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 32.7 %

Procedure:
Following a procedure similar to that described in Example 36, but using 0.30 g of methyl 2-butyl-4-hydroxymethyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 38(c)] and 2.50 ml of a 1N aqueous solution of sodium hydroxide, 95 mg of the title compound were obtained as crystals, melting at 215°-217° C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:14]([CH3:15])[S:13][CH:12]=[N:11]2)[CH:5]=1.[C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH3:26].[Li]>>[C:29]([O:28][C:25](=[O:27])[CH2:26][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:14]([CH3:15])[S:13][CH:12]=[N:11]2)[CH:5]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1cccc(C2(COC3CCCCO3)N=CSC2C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC1SC=NC1(COC1CCCCO1)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
3-[5-Methyl-4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-benzoic acid methyl ester (1.45 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-oxo-3-[3-[5-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-phenyl]-propionic acid tert-butyl ester (2.13 g) as a pale-yellow oil.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[NH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:19][CH2:18]1>>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([F:28])([F:26])[F:27])[CH2:19][CH2:18]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Reactant: c1cc2cc(OC[C@@H]3CO3)ccc2[nH]1
Product: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1ccc2[nH]ccc2c1
Yield: 55.1 %

Procedure:
Prepared from 5-[(2S)-oxiranylmethoxy]-1H-indole (0.050 g, 0.25 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.105 g, 0.5 mmol) according to the procedure used for Example 2 to give 0.055 g of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1)#[CH:2].C#CCCCCCC.[C:26]([O:30][C:31](=[O:50])[NH:32][C:33]1([C:41]#[C:42][C:43]2[CH:48]=[CH:47][C:46](I)=[CH:45][CH:44]=2)[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27].IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:26]([O:30][C:31](=[O:50])[NH:32][C:33]1([C:41]#[C:42][C:43]2[CH:48]=[CH:47][C:46]([C:2]#[C:1][C:3]3[CH:4]=[CH:5][C:6]([C:9](=[O:10])[C:11]4[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=4)=[CH:7][CH:8]=3)=[CH:45][CH:44]=2)[CH2:34][O:35][C:36]([CH3:40])([CH3:39])[O:37][CH2:38]1)([CH3:27])([CH3:28])[CH3:29]
Reactant: C#Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(I)cc2)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(C#Cc3ccc(C(=O)c4ccc(F)cc4)cc3)cc2)COC(C)(C)OC1
Yield: 42 %

Procedure:
When the product of Step D was substituted for 1-octyne and tert-butyl-5-((4-iodophenyl)ethynyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 42% yield, as creamy paste. 1H-NMR (CDCl3) 1.44 (s, 3H); 1.47 (s, 9H); 1.5 (s, 3H); 4.02 (d, 2H, J=11.37 Hz); 4.1 (d, 2H, J=11.31 Hz); 5.2 (s, 1H); 7.16 (tr, 2H, J=8.64 Hz); 7.40 (d, 2H, J=8.49 Hz); 7.46 (tr, 2H, J=8.46 Hz); 7.60 (d, 2H, J=8.43 Hz); 7.74 (d, 2H, J=8.39 Hz); 7.80-7.83 (m, 2H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[N:24]1[CH:32]=[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:26]2=[N:25]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:16]=[C:15]([Cl:23])[C:14]=1[N:24]1[CH:32]=[C:27]2[CH:28]=[N+:29]([O-:9])[CH:30]=[CH:31][C:26]2=[N:25]1
Reactant: CS(=O)(=O)c1cc(Cl)c(-n2cc3cnccc3n2)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(Cl)c(-n2cc3c[n+]([O-])ccc3n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
mCPBA (569 mg, 3.3 mmol) was added to a cooled (0° C.) solution of 2-(2,6-dichloro-4-methanesulfonylphenyl)-2H-pyrazolo[4,3-c]pyridine (752 mg, 2.2 mmol) in DCM (20 mL) under nitrogen. The reaction was stirred for 1 hour, warmed to room temperature, and stirred for an additional 2 hours. Further mCPBA (150 mg) was added and the reaction mixture was stirred at room temperature for 4 hours before adding sodium thiosulfate (aq.). The organic layer was separated, washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (5-10% methanol in DCM) to afford the title compound as a white solid (640 mg, 81% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.94 (dd, J=1.8, 0.9 Hz, 1H), 8.88 (d, J=1.0 Hz, 1H), 8.33 (s, 2H), 7.96 (dd, J=7.5, 1.8 Hz, 1H), 7.86 (dt, J=7.5, 1.0 Hz, 1H), 3.48 (s, 3H). LCMS (Method D): RT=2.13 min, m/z: 358 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10]([Mg]Br)[CH3:11]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2([NH2:9])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1cccc(Cl)n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: NC1(c2cccc(Cl)n2)CC1
Yield: 14.1 %

Procedure:
To a solution of 6-Chloro-pyridine-2-carbonitrile (500 mg, 3.61 mmol) in THF (45 mL) was added titanium isopropoxide (1.59 mL, 5.41 mmol) in one portion followed by ethylmagnesium bromide (3 M in Et2O, 3.6 mL, 11 mmol) slowly over 5 min. The reaction was stirred for 4 then quenched by the addition of water (5 mL). The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated. The resulting material was purified first by flash chromatography (silica, 5→10% MeOH/CH2Cl2) and then by reversed phase HPLC (1→95% MeCN/H2O+0.1% TFA) to give 86 mg of the title compound presumably as the bis-TFA salt, m/z 169.59 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([F:19])=[CH:4][N:3]=1.[Br:20][Si](C)(C)C>C(#N)CC.C(OCC)(=O)C>[Br:20][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([F:19])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)Br
Reactant: Fc1cccc(Cl)c1-n1cc2c(Cl)ncc(F)c2n1
Solvent: CCC#N
Solvent: CCOC(C)=O
Product: Fc1cccc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Temperature: 100 °C
Yield: 100.6 %

Procedure:
4-Chloro-2-(2-chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (3.05 g, 10.1 mmol) was suspended in propionitrile (60 mL) under an atmosphere of nitrogen and bromotrimethylsilane (4.0 mL, 30.0 mmol) was added. The reaction mixture was heated at 100° C. overnight. The resultant mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a beige solid (3.5 g, 100% yield). This was used directly in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 9.46 (d, J=2.5 Hz, 1H), 8.21 (d, J=3.4 Hz, 1H), 7.85-7.77 (m, 1H), 7.74-7.64 (m, 2H).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=O.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]2[CH:47]([N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)[C:42]3=[N:43][CH:44]=[CH:45][CH:46]=[C:41]3[CH2:40][CH2:39][C:38]=2[CH:54]=1.O>CN(C)C=O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]2[CH:47]([N:48]3[CH2:49][CH2:50][N:51]([C:8](=[O:10])/[CH:7]=[CH:6]/[C:2]4[N:3]=[CH:4][NH:5][CH:1]=4)[CH2:52][CH2:53]3)[C:42]3=[N:43][CH:44]=[CH:45][CH:46]=[C:41]3[CH2:40][CH2:39][C:38]=2[CH:54]=1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1c[nH]cn1)N1CCN(C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
To a suspension of urocanic acid (1.38 g; 10.0 mmol) (from Aldrich Chemicals) in N,N-dimethylformamide (175 mL) under an inert atmosphere, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g; 10.0 mmol) and hydroxybenzotriazole (1.08 g; 8 mmol). The resultant mixture was warmed to 40° C. and stirring continued until all solids dissolved (˜10 min.). To the resultant solution was added 8-chloro-6,11-dihydro-11-(1-piperazinyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (8) (2.51 g; 8.0 mmol), and the resultant solution was allowed to stir at room temperature for 18.5 h. Then water (250 microliters; 13.9 mmol) was added, and the solution was stirred briefly before concentrating under reduced pressure. The residual oil was partitioned between dichloromethane (100 mL) and water (100 mL). The organic extract was dried by filtration through anhydrous magnesium sulfate and solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane-methanol-concentrated ammonium hydroxide (90:9:0.5), to obtain the title compound as a yellow powder that decomposed to a frothy gum at 160° C. SIMS: 434 (MH+; 50%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:28][C:29]1[N:30]=[CH:31][N:32]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:33]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cn(CCCC(F)(F)F)cn1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
Cesium carbonate (1.95 g, 6 mmol) and 1-bromo-4,4,4-trifluorobutane (954 mg, 5 mmol) were added to a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-imidazol-4-yl)propanoate (1.08 g, 4 mmol) in N,N-dimethylformamide (5 ml), and the reaction stirred at 70° C. for 3 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (150 ml) and water (50 ml). The layers were separated, the organic phase dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of cyclohexane:ethyl acetate (100:0 to 0:100) to afford the title compound as an oil, 840 mg, 55% yield.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](I)=[CH:7][N:6]=[C:5]([Cl:10])[CH:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([CH:22]=[CH2:23])[CH:13]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:19]([N:18]1[C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[CH:22]=[CH:23][C:8]2[CH:7]=[N:6][C:5]([Cl:10])=[CH:4][C:3]=2[CH2:2]1)(=[O:21])[CH3:20]
Reactant: Clc1cc(CBr)c(I)cn1
Reactant: C=Cc1cc(Cl)ccc1NC(C)=O
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cc(Cl)ncc2C=Cc2cc(Cl)ccc21

Procedure:
The title compound was prepared from 25D and 9B in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.836 min; LCMS Found: (M+H)+=319.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[N:17]=[N:18][NH:19][N:20]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[N:33]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])[O:31][N:30]=3)=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].C([SiH](C(C)C)C(C)C)(C)C>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[NH:17][N:18]=[N:19][N:20]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]3[N:33]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])[O:31][N:30]=3)=[CH:25][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]
Reactant: COc1ccccc1-c1nc(COc2ccc(-c3nc4cc(-c5nn[nH]n5)ccc4n3C3CCCCC3)cc2)no1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1nc(COc2ccc(-c3nc4cc(-c5nnn[nH]5)ccc4n3C3CCCCC3)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 37 from the preceding experiment was added to 2.0 mL of methylene chloride:TFA:triisopropylsilane (6:2:0.5). The mixture was shaken at rt for 20 min and was filtered. The resin was washed with methylene chloride (2×2 mL). The washings and filtrate were combined and concentrated on a rotary evaporator to afford 34 as a TFA salt (56 mg, 70% yield). ESI MS m/e 549 (M+1). The product was identical to that described in Example 5.