Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:11](=O)[NH:12][C:13]([Cl:15])=[CH:14][C:8]3[C:9]=2[CH:4]([CH2:5][CH2:6][CH:7]=3)[CH2:3]1.B(F)(F)F.CO>C1COCC1>[CH3:1][CH:2]1[C:10]2[CH2:11][NH:12][C:13]([Cl:15])=[CH:14][C:8]3[C:9]=2[CH:4]([CH2:5][CH2:6][CH:7]=3)[CH2:3]1
Reactant: CC1CC2CCC=C3C=C(Cl)NC(=O)C1=C32
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CC1CC2CCC=C3C=C(Cl)NCC1=C32
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 600 mg (2.5 mmol) of 2-methyl-3-oxo-5-chloro-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine, a compound of Formula 16 prepared, for example, as described in Preparation 16, dissolved in 25 ml of THF was combined with 8 ml of a 1M solution of BF3.THF in tetrahydrofuran. The reaction mixture was stored at ambient temperature for 16 hours. A few ml of methanol was added dropwise and the solvents were removed under vacuum. The residue was treated with 25 ml of 5% HCl and digested on a steam bath for 3 hours. After cooling to ambient temperature, the aqueous solution was washed once with ether, made alkaline with NaOH, and extracted with ether. The ether extract was concentrated to give 2-methyl-5-chloro-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine, a compound of Formula I, as the free base; (HBr salt, ethanol, mp 279°-281° C.).
Reaction SMILES: BrC1C=CC2C3N=C(N4C(C)=NN(C)C4=O)SC=3CCOC=2C=1.[I:24][C:25]1[CH:46]=[CH:45][C:28]2[C:29]3[N:30]=[C:31](N4C(C)=NN(C)C4=O)[S:32][C:33]=3[CH2:34][CH2:35][O:36][C:27]=2[CH:26]=1.[CH:47]([N:50]1[C:54](=[O:55])[NH:53][C:52]([CH3:56])=[N:51]1)([CH3:49])[CH3:48].BrC1C=CC2C3N=C(N4C(C)=NN(C(C)C)C4=O)SC=3CCOC=2C=1>>[I:24][C:25]1[CH:46]=[CH:45][C:28]2[C:29]3[N:30]=[C:31]([N:53]4[C:52]([CH3:56])=[N:51][N:50]([CH:47]([CH3:49])[CH3:48])[C:54]4=[O:55])[S:32][C:33]=3[CH2:34][CH2:35][O:36][C:27]=2[CH:26]=1
Reactant: Cc1nn(C)c(=O)n1-c1nc2c(s1)CCOc1cc(I)ccc1-2
Reactant: Cc1nn(C(C)C)c(=O)[nH]1
Agent: Cc1nn(C(C)C)c(=O)n1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cc1nn(C)c(=O)n1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: Cc1nn(C(C)C)c(=O)n1-c1nc2c(s1)CCOc1cc(I)ccc1-2

Procedure:
Following a similar procedure for the mixture of 4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one and 4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one using 2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one, the mixture of 4-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one and 4-(8-Iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one (˜1:1) was isolated as an off-white solid (49 mg). LCMS: RT=5.17 min, [M+H]+=421/423 and 469
Reaction SMILES: [C:1]1([S:7][C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O:18]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]1([S:7][C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([OH:18])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=C(Sc2ccccc2)CC2CC(=O)C12
Yield: 84.1 %

Procedure:
A solution of 150 mg of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, and 135 mg of anisole in 3 mL of trifluoroacetic acid was stirred at room temperature for 15 min. The solvent was removed with a stream of nitrogen leaving a residual oil which when triturated with ether afforded 77 mg (84%) of colorless crystals of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid. NMR (220 MHz; CDCl3): δ 2.27 (1H, dd, J=17, 3), 2.75 (1H, m), 2.68 (1H, m), 3.0-3.25 (1H, m), 4.50 (1H, m), 7.2-7.4 (3H, m), and 7.4-7.6 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:10])[CH2:5]2.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.[CH2:27](OCC)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[C:6]([CH2:27][C:15]1[CH:14]=[C:13]([C:12]([F:26])([F:25])[F:11])[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1)([OH:10])[CH2:5]2
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Reactant: CCOCC
Reactant: O=C1Cc2cc(Br)ccc21
Product: OC1(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(Br)ccc21
Yield: 76 %

Procedure:
Using 3-bromobicyclo[4.2.0]octa-1,3,5-triene-7-one (3) (2.0 g, 0.015 mol), diethyl ether (20 ml), 3,5-bis(trifluoromethyl)phenyl magnesium bromide (3M in diethyl ether, 3.8 ml, 11.7 mmol) afforded 3-Bromo-7-(3′,5′-bis(trifluoromethyl)benzyl)-bicyclo[4.2.0]octa-1,3,5-triene-7-ol (4b) (3.17 g, GC-MS: M+=410, M−=412, 76% yield, isolated as a mixture of isomers).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O.[CH2:20]([O:27][C:28]([NH:30][CH:31](P(OC)(OC)=O)[C:32]([O-:34])=[O:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:41]1CCN2C(=NCCC2)CC1.C(OCC)(=O)C>ClCCl>[CH3:41][O:34][C:32](=[O:33])[C:31]([NH:30][C:28]([O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:29])=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH2:8][NH:9][C:10]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:16])[CH:17]=1
Reactant: COP(=O)(OC)C(NC(=O)OCc1ccccc1)C(=O)[O-]
Reactant: COc1ccc(C=O)cc1CNC(=O)OC(C)(C)C
Reactant: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2.65 g of t-butyl N-(5-formyl-2-methoxybenzyl)carbamate, 3.81 g of methyl 2-([(benzyloxy)carbonyl]amino-2-(dimethoxyphosphoryl)acetate and 1.75 g of 1,8-diazabicyclo[5,4,0]-7-undecene were dissolved in 50 ml of dichloromethane, followed by stirring for 15 hours at room temperature. 300 ml of ethyl acetate was added, and the organic layer was successively washed with 150 ml of water and 150 ml of brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, and 4.09 g of 2-{[(benzyloxy)carbonyl]amino}-3-(3-{[(t-butoxycarbonyl)amino]methyl}-4-methoxyphenyl)-2-propenoic acid methyl ester was obtained as a colorless solid.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O1CC[N:21]([CH:24]=[CH:25][CH2:26][CH3:27])CC1>>[CH2:26]([C:25]1[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:21][CH:24]=1)[CH3:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Reactant: CCC=CN1CCOCC1
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Reaction time: 72 h
Yield: 56.9 %

Procedure:
Diethyl ethoxymethyleneoxalacetate (3.17 g, 0.013 mol) is added to a solution of 1-morpholinobutene (1.84 g, 0,013 mol) dissolved in CH2C12 (40 mL) at 0°. The solution is concentrated in vacuo, and ammonium acetate (50 g), ammonium hydroxide (10 mL), tetrahydrofuran (20 mL) and 95% ethanol (20 mL) are added. The solution is heated to reflux for 30 minutes, then held at 3° for 72 hours. The reaction solution is then partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo to give the product (1.85 g, 0.0074 mol, 57%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[F:29])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O.C(Cl)Cl>[F:29][C:19]1[CH:20]=[C:21]([O:24][C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(OC(F)(F)F)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(OC(F)(F)F)cc1F
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (3.22 g, 7.40 mmol) was dissolved in MeOH (30 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.311 g, 7.77 mmol) dissolved in water (3.00 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.476 mL, 7.77 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (38.2 mL, 229.28 mmol) and the mixture was stirred at 80° C. for 15 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (4 runs) (10 μm 250×50 ID mm) using a gradient of 25-65% Acetonitrile in H2O/MeCN/HOAc 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.82 g, 61%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.82-1.91 (m, 1H), 2.03-2.13 (m, 1H), 2.22-2.41 (m, 2H), 3.01-3.10 (m, 1H), 3.43-3.53 (m, 1H), 3.63 (s, 3H), 4.11-4.21 (m, 1H), 5.19 (dd, 1H), 5.59 (s, 1H), 6.89-6.95 (m, 2H), 7.14 (t, 1H). MS m/z 405 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12]>>[C:11]([C:13](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:14]([NH2:16])=[O:15])#[N:12]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: N#CCC(N)=O
Product: N#CC(=Cc1ccc(O)c(O)c1)C(N)=O
Yield: 71 %

Procedure:
Reaction of 2.4 g (10 mmol) 3,4-dihydroxybenzaldehyde and 0.9 g (10.7 mmol) cyanoacetamide by the procedure described in Example 1 above gave 1.45 g (70% yield) of product as a yellow solid, m.p. 247° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:16]([C:17]([NH2:19])=[O:18])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:8](=[O:9])[CH2:7][C:5]=2[CH:6]=1.[C:20](OCC)(=[O:22])[CH3:21].O.C(O)=O>CN(C)C=O>[CH3:21][C:20]([O:9][C@@H:8]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[N:16]([C:17]([NH2:19])=[O:18])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH2:7]1)=[O:22]
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Solvent: O=CO
Product: CC(=O)O[C@H]1Cc2ccccc2N(C(N)=O)c2ccccc21
Reaction time: 29 h

Procedure:
In a 250 ml flask with overhead stirrer, reflux condenser and under nitrogen were combined: 16 g oxcarbazepine (63 mmol, 1 mol eq), 120 ml of ethyl acetate, 35 g IRA-67 tertiary ion exchange resin (SigmaAldrich, cat 476633), 10 ml water and 4.4 g formic acid (96 mmol, 1.5 mol eq). 35 mg RuCl [(S,S)-Ts-DPEN](p-cymene) (SigmaAldrich #703915) was dissolved in 10 ml dimethylformamide and added to the reactor. The reaction was heated in an oil bath to reflux. After 29 hours, without any further formic acid addition, the conversion had reached 98,4%. Product was isolated by filtering off the resin and washing with a 20 ml ethyl acetate. The combined organic phases were then washed with 10 ml water which was separated off. After cooling in the fridge, the product was filtered off and washed twice with 15 ml ethyl acetate. The isolated product had an ee of 98%. After acetylation and crystallisation using a similar method to that described in Example 3, eslicarbazepine acetate was isolated with an ee of 99.8% and product purity of 99.9% (HPLC area %, 210 nm).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:34])=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH3:35].CO>>[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:34])=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: N
Solvent: CO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 45 °C

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (200 mg, 0.381 mmol) and ammonia in MeOH 7M (6 ml, 42.0 mmol) and heating to 45° C. overnight, the title compound was obtained as a light yellow solid (128 mg, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.84 (s, 1H), 7.93 (d, J=5.2 Hz, 1H), 7.55-7.70 (m, 1H), 7.34-7.43 (m, 1H), 7.30 (t, J=6.3 Hz, 1H), 7.13-7.27 (m, 3H), 6.71 (s, 2H), 5.79 (d, J=5.1 Hz, 1H), 3.17-3.27 (m, 1H), 1.30 (d, J=6.9 Hz, 6H). MS (ESI): 506.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:24]Br)=[O:5])[CH3:2].[CH2:26]([O:28][C:29](=[O:43])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[O:41][CH3:42])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:24][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[O:41][CH3:42])[CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(Oc3ccccc3)cc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.8 %

Procedure:
A mixture of 4-bromomethyl-2-(4-phenoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.12 g, 2.68 mmole), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (737 mg, 2.90 mmole) and potassium carbonate (555 mg, 4.03 mmole) in anhydrous dimethylformamide (8 ml) was stirred at room temperature for 20 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (1.20 g). MS: (+) m/z 613.07 (M+Na+).
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:30])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)CCC>[CH3:13][O:12][C:9]1[C:8](=[O:14])[N:7]([CH3:15])[C:6]2[N:5]=[CH:4][N:3]=[C:2]([N:16]3[CH2:21][CH2:20][C:19]4([C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][C:22]4=[O:30])[CH2:18][CH2:17]3)[C:11]=2[N:10]=1
Reactant: COc1nc2c(Cl)ncnc2n(C)c1=O
Reactant: O=C1Nc2ccccc2C12CCNCC2
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1nc2c(N3CCC4(CC3)C(=O)Nc3ccccc34)ncnc2n(C)c1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Into a 100 mL round bottomed flask were placed 4-Chloro-6-methoxy-8-methylpteridin-7(8H)-one (2.00 g, 8.83 mmol, 1 equiv) and spiro[indoline-3,4′-piperidin]-2-one (2.14 g, 10.6 mmol, 1.2 equiv). Anhydrous n-butanol (20 mL) and triethylamine (2.46 mL, 2 equiv) were added and reaction mixture was heated to 80° C. with stirring. The reaction was complete as monitored by LC/MS after 5 hours. The solvent was stripped by rotary evaporation, and the residue rinsed with water (5 mL) to yield a tan precipitate, which was collected by vacuum filtration and rinsed with water to afford the desired product which was used directly without any further purification. 1H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.39 (s, 1H), 7.49 (d, 1H), 7.20 (d, 1H), 6.97 (t, 1H), 6.87 (t, 1H), 4.53-4.45 (m, 4H), 3.80 (s, 3H), 3.55 (s, 3H), 1.93-1.80 (m, 4H). MS (EI) for C20H20N6O3: 393 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([S:53]([C:56]2[CH:61]=[CH:60][C:59]([NH:62][C:63]3[N:68]=[CH:67][C:66]([NH2:69])=[CH:65][N:64]=3)=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:40]([O:44][C:45]([N:47]1[CH2:48][CH2:49][CH:50]([S:53]([C:56]2[CH:57]=[CH:58][C:59]([NH:62][C:63]3[N:68]=[CH:67][C:66]([NH:69][C:4](=[O:6])[C:3]4[CH:7]=[C:8]([NH:11][C:12](=[O:21])[C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)[CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:65][N:64]=3)=[CH:60][CH:61]=2)(=[O:54])=[O:55])[CH2:51][CH2:52]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 17 (Example 25) (0.134 g, 0.439 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were used as-is for deprotection step. White solids (0.075 g, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:24])[C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25]([N:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:29][CH2:30][CH:31]([C:34]([N:11]2[CH2:12][CH2:13][C@@H:14]([N:15]([CH3:24])[C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10]2)=[O:35])[CH2:32][CH2:33]1)(=[O:27])[CH3:26]
Reactant: CN(C(=O)c1ccccc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccccc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 14 and 1-acetylpiperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])C(F)(F)F)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[OH-:31].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])=[O:31])=[CH:7][N:8]2[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: [OH-]
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC2CCCCC2)c2cc(Cl)ccc12
Temperature: 60 °C
Yield: 70 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (300 mg, 1.21 mmol), potassium carbonate (419 mg, 3.03 mmol), and bromomethylcyclohexane (0.25 mL, 1.82 mmol) in N,N-dimethylformamide (4 mL) in a sealed reaction vessel was heated at 60° C. for 6 h. At this time, the reaction was cooled to 25° C. and partitioned between water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (15 mL), shaken, and separated. The organic layer was concentrated in vacuo to afford an orange oil. The resulting oil was treated with a 20% aqueous sodium hydroxide solution (7 mL) and was heated at 110° C. for 40 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (50 mL) and ethyl acetate (50 mL). This solution was treated with a 1N aqueous hydrochloric acid solution (20 mL), shaken, and separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to provide a yellow solid. The resulting solid was slurried in a solution of 3/1 hexanes/ethyl acetate for 5 min. The solid was then collected by filtration to afford 6-chloro-1-cyclohexylmethyl-1H-indole-3-carboxylic acid (247 mg, 70%) as a pale yellow solid: mp 170-172° C.; EI-HRMS m/e calcd for C16H18ClNO2 (M+) 291.1026, found 291.1026.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:36][Mg]Br.C(OCC)C>O1CCCC1>[F:35][C:2]([F:1])([F:34])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([C:20]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=3)([OH:21])[CH3:36])[CH2:18][CH2:19]2)=[CH:32][CH:33]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(=O)Nc1ccc(C(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(C)(O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-(4-(1-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidine-4-carbonyl)phenyl)acetamide (1.702 mmol, 855 mg) was dissolved in anhydrous tetrahydrofuran (20 mL) under nitrogen and cooled to −78° C. 3M methylmagnesium bromide in diethyl ether (3.40 mmol, 1.134 mL) was added and the mixture stirred at −78° C. for 30 minutes before allowing to warm to room temperature and stirring for a further 4 hours. After this time, further 3M methylmagnesium bromide in diethyl ether (3.40 mmol, 1.134 mL) was added and the mixture stirred for 2 hours. The mixture was cooled to 0° C. and quenched with a saturated solution of ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (100 mL) and washed with water (30 mL) then brine (30 mL). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with dichloromethane to 15% methanol/dichloromethane) to afford the title compound (300 mg). MS (ESI) m/z 519.2 [M+H]+