Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:43]([CH2:44][CH2:45][CH3:46])=[C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[C:26]([S:28]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]4)(=[O:30])=[O:29])[CH:25]=[CH:24][C:23]=3[O:39][CH2:40][CH2:41][CH3:42])[NH:19][C:20](=[O:21])[C:15]2=[N:14]1>N1C=CC=CC=1>[CH2:37]([N:34]1[CH2:35][CH2:36][N:31]([S:28]([C:26]2[CH:25]=[CH:24][C:23]([O:39][CH2:40][CH2:41][CH3:42])=[C:22]([C:18]3[NH:19][C:20](=[O:21])[C:15]4[C:16](=[C:43]([CH2:44][CH2:45][CH3:46])[N:13]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=5[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=4)[N:17]=3)[CH:27]=2)(=[O:30])=[O:29])[CH2:32][CH2:33]1)[CH3:38]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CCC)n(-c3ccccc3N)nc2c(=O)[nH]1
Solvent: c1ccncc1
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CCC)n(-c3ccccc3NS(C)(=O)=O)nc2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
Methanesulphonyl chloride (0.156 ml, 2.0 mmol) was added to a stirred solution of the title compound of Example 116 (583 mg, 1.0 mmol) in pyridine (8 ml), under nitrogen, and the resulting solution stirred at 50° C. for 18 hours, then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water, then the separated organic phase washed with brine, dried (MgSO4) and evaporated under reduced pressure. The resulting brown foam was purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (100:0 to 99:1 to 98:2 to 97:3), to yield the title compound (32%) as a cream foam. Found: C, 53.96; H, 6.01; N, 14.38. C30H39N7O6S2; 0.60 H2O requires C, 53.89; H, 6.06; N, 14.67%. δ (CDCl3): 0.91 (3H, t), 1.01 (3H, t), 1.19 (3H, t), 1.75 (2H, m), 2.07 (2H, m), 2.40 (2H, q), 2.53 (4H, m), 2.93 (2H, t), 3.07 (3H, s), 3.09 (4H, m), 4.29 (2H, t), 7.16 (2H, m), 7.35 (2H, m), 7.57 (1H, t), 7.82 (2H, d), 8.80 (1H, s), 10.74 (1H, s). LRMS: m/z 658 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[C:9]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)=[CH:4][CH:3]=1.O1CCOCC1.[ClH:33]>>[ClH:33].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:10][NH:11][C:12]2=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1
Yield: 96 %

Procedure:
In a round bottom flask under nitrogen, 1,1-dimethylethyl (3S)-3-{[4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-1-pyrrolidinecarboxylate (3.54 mmol) in 4M HCl in dioxane (40 mmol) was stirred at room temperature for 2 h. The solvent was removed by concentration in vacuo to give the title compound as the HCl salt (1.25 g, 96% yield). MS(ES)+ m/e 322.9, 325.0 [M+H]+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][CH2:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[OH:29])=O)=[CH:17][CH:16]=1.O.CCCCCC>ClC1C=CC=CC=1Cl>[Cl:13][CH2:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]2[O:29][C:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[N:21]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(O)c(NC(=O)c2ccc(CCl)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1Cl
Solvent: CCCCCC
Product: Cc1ccc2oc(-c3ccc(CCl)cc3)nc2c1
Temperature: 175 °C

Procedure:
With stirring, 5 g (26.3 mmol) of p-toluenesulphonic acid monohydrate were added to 116 g (about 406 mmol) of 4-(chloromethyl)-N-(2-hydroxy-5-methylphenyl)benzamide in 700 ml of 1,2-dichlor-obenzene. The reaction solution was then heated to 175° C. (oil bath temperature) and stirred at this temperature on a water separator for 3 hours. The reaction solution was then cooled to room temperature, 200 ml of hexane were added and the mixture was stirred for about 1 hour. The precipitated solid was filtered off, washed with hexane and air-dried. This gave 56 g (217.29 mmol, 53% of theory) of the target compound.
Reaction SMILES: [Li+].[OH-].C([O:6][C@@H:7]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][C@H:26]([OH:33])[C@@:25]2([CH3:34])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[CH2:8]1)(=O)C>O.C1COCC1.CO>[CH3:24][C@@H:17]([C@@H:16]1[C@@:25]2([CH3:34])[C@@H:26]([OH:33])[CH2:27][C@@H:28]3[C@@:29]4([CH3:32])[CH2:30][CH2:31][C@@H:7]([OH:6])[CH2:8][C@H:9]4[CH2:10][CH2:11][C@H:12]3[C@@H:13]2[CH2:14][CH2:15]1)[CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 91.8 %

Procedure:
A solution of LiOH (187 mg, 4.4 mmol) in H2O (2.0 mL) was added to a solution of compound 2.1a (500 mg, 1.11 mmol) in THF (8 mL) and MeOH (8 mL). The resulting mixture was stirred for 3-4 h at 50° C. Upon complete disappearance of the starting material by TLC, the reaction mixture was concentrated under vacuum. A mixture of water (10 mL) and 3 N HCl (1 mL) were combined and cooled to 0° C. and then added to the crude product. After stirring for 1 h at 0° C., the precipitated solids were filtered and then washed with water (10 mL) and hexane (20 mL). Drying under vacuum at room temperature provided deoxycholic acid (DCA, 400 mg, 91% yield) as a white solid.
Reaction SMILES: C1(N2CC[O:10]CC2)CCCCC=1.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].Cl.[C:26]1(C)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:20]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C:26]1=[O:10])(=[O:23])[CH2:21][CH3:22]
Reactant: Cc1ccccc1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCC(=O)C1CCCCC1=O
Yield: 49 %

Procedure:
Compound IVb is obtained in 49% yield as a colourless oil, according to Example 4, from 4-cyclohex-1-enyl-morpholine (82.64 g, 0.50 mol, obtained in Example 1), triethylamine (71.33 g, 1.41 mol), propionyl chloride (64.76 g, 1.41 mol), toluene (770 mL) and 20% aqueous HCl (250 mL).
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:5]=[C:6]2[C:36](=[CH:37][CH:38]=1)[C:14]1[N:15]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:16]([C:18]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[N:17][C:13]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:39][C:40](=[O:42])[CH3:41])=[CH:8][C:7]2=1>C(OCC)C.Cl[Ti](Cl)(Cl)Cl>[Cl:3][C:4]1[CH:5]=[C:6]2[C:36](=[CH:37][CH:38]=1)[C:14]1[N:15]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:16]([C:18]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[N:17][C:13]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:39][C:40]([OH:42])([CH3:1])[CH3:41])=[CH:8][C:7]2=1
Reactant: [Li]C
Reactant: CC(=O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a round bottomed flask at −78° C. charged with TiCl4 (1 M in CH2Cl2, 20 mL), was added methyllithium (1.6 M in diethyl ether, 12.5 mL). The resulting deep red solution was stirred at −78° C. for 15 minutes and then added via cannula to a 0° C. solution of 2-(9-chloro-6-(2-oxopropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl)-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (2.8 g, 5.0 mmol) from Step 2 above, in diethyl ether (10 mL). The resulting mixture was stirred at 0° C. for 3 h, then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography on silica (50% ethyl acetate in hexanes) to provide 2-(9-chloro-6-(2-hydroxy-2-methylpropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (1.94 g),
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[F:12].[Cl:13]N1C(=O)CCC1=O.[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:13][C:4]1[C:3]([F:12])=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1cc2ccncc2cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Fc1c(Cl)cc2cnccc2c1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
5.0 g (27.5 mmol) 7-Chloro-6-fluoro-isoquinoline (150) were dissolved in 90 ml of conc. sulphuric acid. At room temperature 7.35 g (55.0 mmol) N-Chlorosuccinimide were added and the mixture was stirred at 50° C. After standing overnight at room temperature another 3 eq. N-Chlorosuccinimide were added and at the following again 5 eq. N-Chlorosuccinimide were added and the temperature was increased to 80° C. After no further conversion could be detected, the mixture was cooled to room temperature and poured on ice. The aqueous solution was brought to basic pH by adding solid NaOH. The precipitate was filtered off and washed three times with dichloromethane. After drying the organic filtrates with MgSO4 and evaporation of the solvent 1.09 g of the desired isoquinoline could be isolated. Rt=1.26 min (Method #TOP). Detected mass: 216.0/218.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[CH:19][CH:18]=2)([C:12](OC)=[O:13])[C:8](OC)=[O:9])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])=[CH:21][CH:22]=2)([CH2:12][OH:13])[CH2:8][OH:9])=[CH:30][CH:31]=1
Reactant: CCOC(OCC)c1ccc(CC(Cc2ccc(Br)cc2)(C(=O)OC)C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(CC(CO)(CO)Cc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution Dimethyl 2-(4-bromobenzyl)-2-[4-(diethoxymethyl) benzyl]malonate(crude from Step 2) in 200 mL of THF cooled at 0° C. was added of LiAlH4 (0.8 g). The mixture was stirred for 2 h at room temperature and the quenched with acetone (5 mL), followed by 100 mL of 20% aqueous sodium potassium tartrate solution. The mixture was extracted with 200 ML of 2:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel chromatography eluted with 2:1 hexane EtOAc containing 1% of Et3N to give 4.2 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][NH:28][C:29](=[NH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]2[N:36]=[C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)[O:27][N:28]=2)[CH:31]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1cccnc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5cccnc5)no4)c3n2)cc1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) and commercially available N-hydroxy-nicotinamidine [CAS-No. 1594-58-7] (103 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane/MeOH/hexane) as a yellow solid (126 mg, 53%). MS (EI) 476.1 [(M+H)+]; mp 199° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2([C:28]([NH:15][C:13]3[N:14]=[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:3]5[CH:4]=[CH:5][O:1][CH:2]=5)[N:11]4[N:12]=3)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CCCC1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)C1(c2ccc(Cl)cc2)CCCC1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 1-(4-chlorophenyl)-1-cyclopentanecarbonyl chloride (Lancaster, 91 mg; 0.37 mmol; 1.5 eq.) as a white foam (61.1 mg, 60%). HPLC, Rt: 4.64 min. (purity 73.4%). LC/MS, M+(ESI): 407.4, M−(ESI): 405.4.
Reaction SMILES: [CH3:1][CH:2]([NH2:26])[CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:4]C1C=C2C(=CC=1)N(C1C=CC=CN=1)N=C2.[Cl:27][C:28]1[N:33]=[N:32][C:31]([N:34]2[C:42]3[C:37](=[CH:38][C:39](I)=[CH:40][CH:41]=3)[CH:36]=[N:35]2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[N:33]=[N:32][C:31]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([O:4][CH:3]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:2]([NH2:26])[CH3:1])=[CH:40][CH:41]=3)[CH:36]=[N:35]2)=[CH:30][CH:29]=1
Reactant: Clc1ccc(-n2ncc3cc(I)ccc32)nn1
Reactant: CC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Product: CC(N)C(Oc1ccc2c(cnn2-c2ccc(Cl)nn2)c1)c1ccccc1

Procedure:
Prepared as described for 118a using 1-(6-Chloro-pyridazin-3-yl)-5-iodo-1H-indazole (119b). Yield 35 mg (7%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[CH2:12]([NH:14][C:15]([C:17]1[S:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2Cl)[CH:18]=1)=[O:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([C:17]1[S:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:18]=1)=[O:16])[CH3:13]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CCNC(=O)c1cc2nccc(Cl)c2s1
Product: CCNC(=O)c1cc2nccc(Nc3ccc4[nH]c(C)cc4c3)c2s1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid ethylamide by a procedure analogous to Example 1C. MS: 351 (MH+); HPLC Rf: 4.33 min; HPLC purity: 98%.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[C:13]2[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[N:11][C:10]([NH:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:9][C:8]=2[CH2:7]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>>[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].[NH2:27][CH2:26][CH2:25][NH:24][C:10]1[N:11]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[C:13]2[C:14](=[O:15])[NH:6][CH2:7][C:8]=2[N:9]=1
Reactant: COc1ccc(CN2Cc3nc(NCCNC(=O)OC(C)(C)C)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(NCCN)nc3c2C(=O)NC3)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
A mixture of tert-butyl 2-(6-(2,4-dimethoxybenzyl)-5-oxo-4-(m-tolylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-ylamino)ethylcarbamate (0.055 g, 0.100 mmol) in TFA (2 mL) was stirred at 70° C. for 1.5 h. Following reaction, the solvent was removed and the resulting residue was dispersed into a solution of DMSO and MeOH (1/1). The mixture was filtered and the filtrate was purified by preparative HPLC. The fractions were collected and dried in vacuo to give a TFA salt of the title compound as an off-white solid (28 mg, 93%). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.21-2.40 (m, 3H) 2.90-3.21 (m, 2H) 3.57 (q, J=5.86 Hz, 2H) 4.19 (br s, 2H) 6.90 (br s, 1H) 7.13-7.34 (m, 1H) 7.54 (br s, 1H) 7.56-7.74 (m, 2H) 7.80 (br s, 2H) 8.18 (d, J=13.67 Hz, 1H) 8.54-8.82 (m, 1H). [M+H] calc'd for C15H18N6O, 299. found, 299.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[C@H:20]12[NH:27][CH2:26][C@H:25]1[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:21]2.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:3]=1[C:4]([N:27]1[C@H:20]2[C@H:25]([CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:21]2)[CH2:26]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)c3c(F)cccc3-n3nccn3)[C@@H]2C1
Temperature: 50 °C
Reaction time: 15 h
Yield: 64.2 %

Procedure:
To 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (406 mg, 1.5 mmol) in PhCH3 (5 mL) was added SOCl2 (117 μL, 1.6 mmol). The flask was heated with an oil bath to 50° C. for 1 h. To (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (260 mg, 1.3 mmol) and Na2CO3 (519 mg, 4.9 mmol) in PhCH3 (5 mL) and H2O (5 mL) at 0° C. was added the above solution dropwise. The reaction was allowed to warm slowly to rt and stir for 15 h and extracted with DCM (2×). The combined organics were dried (Na2SO4). Purification via silica gel chromatography (1-7% 2M NH3/MeOH in CH2Cl2) gave 335 mg (68%) of the title compound. MS (ESI) mass calcd. C20H24FN5O3, 401.44; m/z found 346.1 [M−C(CH3)3]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>O1CCCC1>[NH2:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([O:20][C@H:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N+:4]([O-:33])=[CH:5][C:6]=1[Cl:32])=[O:31]
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(N)c2)cc1OC
Temperature: 75 °C
Yield: 86.3 %

Procedure:
To a stirred solution of [(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]-3-nitrobenzoate (0.640 g, 1.30 mmol) in anhydrous tetrahydrofuran (30.0 mL) was added tin chloride dihydrate (1.18 g, 5.2 mmol). After heating at 75° C. for 16 hours, the reaction was allowed to cool to room temperature. The reaction was partitioned between ethyl acetate and sodium bicarbonate and extracted with ethyl acetate (×2). The combined organic extracts were dried on magnesium sulphate, filtered and the solvent was removed in vacuo to afford the title compound as a brown solid (0.520 g, 87% yield).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[C@:18]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:27])[CH2:17]2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]2[C@@:18]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:2][CH:3]4[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]4)[C:19]3=[O:27])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: ClCC1CCNCC1
Product: O=C1N(CC2CCNCC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 70 starting from 4-(chloromethyl)piperidine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C22H23ClN2O: 366, observed (M+H)+: 367.2 1HNMR (400 MHz, MeOD-d4) δppm 1.51-1.67 (m, 2 H) 1.96 (br. s., 2 H) 2.12-2.21 (m, 2 H) 2.21-2.35 (m, 1 H) 2.93-3.07 (m, 2 H) 3.22 (t, J=8.59 Hz, 1 H) 3.38-3.50 (m, 2 H) 3.84 (d, J=7.33 Hz, 2 H) 6.09 (d, J=7.58 Hz, 1 H) 6.77 (t, J=7.58 Hz, 1 H) 7.11 (d, J=7.83 Hz, 1 H) 7.16-7.26 (m, 3 H) 7.29-7.35 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: CCOC(=O)CN=C=O
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CNC(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and ethyl isocyanatoacetate as starting materials in 35% yield. LCMS for C29H33ClN7O4 (M+H)+: m/z=578.2.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[O:33])=[CH:4][CH:3]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: COc1ccccc1N=C=O
Product: COc1ccccc1NC(=O)NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 2-methoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](O)=[O:17])=[CH:8]1.[NH2:20][CH2:21][C:22]1[C:23]([OH:30])=[N:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[OH:30][C:23]1[C:22]([CH2:21][NH:20][C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[CH:8]=2)=[O:17])=[C:27]([CH3:28])[CH:26]=[C:25]([CH3:29])[N:24]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1ccccc1-n1cc(C(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cn(-c3ccccc3C)c3ccccc23)c(O)n1

Procedure:
A mixture of 1-(o-tolyl)-1H-indole-3-carboxylic acid (100 mg, 0.398 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (60 mg, 0.398 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.597 mmol). N-hydroxybenzotriazole (81 mg, 0.597 mmol), triethylamine (81 mg, 0.796 mmol) and dichloromethane (5 mL) was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and ethyl acetate (10 mL) was added. The resulting mixture was washed with water (10 mL) and brine in turns and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative-TLC (silica gel, dichloromethane:methanol=15:1) to give pure desired product of N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-1-(o-tolyl)-1H-indole-3-carboxamide as an off white solid (100 mg, 65%). LRMS (M+H+) m/z: calcd 385.18. found 385. 1H NMR (300 MHz, CD3OD) δ 8.16 (dd, J=6.1, 2.5 Hz, 1H), 7.87 (s, 1H), 7.44 (d, J=4.9 Hz, 2H), 7.41-7.26 (m, 2H), 7.26-7.12 (m, 2H), 6.93 (dd, J=6.3, 2.4 Hz, 1H), 6.11 (s, 1H), 4.53 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.01 (s, 3H).