Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:13]=[C:14]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[O:17][C:16]2[CH:24]=[CH:25][C:26]([C:28](Cl)=[O:29])=[CH:27][C:15]1=2.S(=O)(=O)(O)O>O.C(O)C.ClC1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[O:13]=[C:14]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[O:17][C:16]2[CH:24]=[CH:25][C:26]([C:28]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:29])=[CH:27][C:15]1=2
Reactant: O=C(Cl)c1ccc2oc3ncccc3c(=O)c2c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc2oc3ncccc3c(=O)c2c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
0.57 g of magnesium, 0.8 ml of carbon tetrachloride and 3.6 ml of absolute ethanol are placed in a four-necked flask fitted with a dropping funnel, a thermometer, a reflux condenser and a stirrer. 36.5 ml of chlorobenzene is added, and then a mixture of 2.67 g of diethyl malonate, 18 ml of chlorobenzene and 12.6 ml of absolute ethanol is added dropwise, while the temperature is maintained at 65°C. The mixture is allowed to stand at 85°C for 1 hour to complete the reaction. After cooling with water, 4 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid chloride is added, and the mixture is stirred at 30°-35°C for 1.5 hours. To the reaction mixture is added a mixture of 1 ml of concentrated sulfuric acid and 7 ml of water is added dropwise with stirring under ice cooling, and the precipitate (sodium sulfate) is removed by filtration. The residue is washed with water, dried, and concentrated. The residue is recrystallized from ethanol to give diethyl 2-(5-oxo-5H-[1]benzopyrano[2,3-b]pyridine- 7-yl-carbonyl)malonate as white crystals melting at 137°-138.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:25][OH:26])[CH2:24][CH2:23][CH2:22]2)=[C:17]([O:27][CH3:28])[CH:16]=1.Cl>[OH-].[Na+].CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:25][OH:26])[CH2:24][CH2:23][CH2:22]2)=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CCC4)c(OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1C1(CO)CCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 11.8 %

Procedure:
The mixture of methyl 6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]-3-methoxyphenyl}-1H-indole-3-carboxylate (220 mg, 0.55 mmol) in aqueous sodium hydroxide (10%, 3 mL) and methanol (5 mL) was stirred at 80° C. for 16 hours. The mixture was acidified by concentrated HCl to pH˜4 and extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue, which was purified by reverse phase HPLC to give the title compound (25 mg, 12%) as a white solid. MS (AP+) 368.1 (M−H2O+H)+, 408.1 (M+Na)+. 1H NMR (500 MHz, CD3OD) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 7.08 (d, 1H), 6.98 (d, 2H), 3.86 (s, 2H), 3.80 (s, 3H), 2.36 (m, 4H), 2.11 (m, 1H), 1.86 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[C:10]1(=[O:20])[O:15][C:13](=O)[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.S([O-])(O)(=O)=O.[K+]>C(OCC)(=O)CCCCCCCCCCC>[CH3:1][C:2]1[C:3]2[O:4][C:8]3[C:2]([CH3:1])=[C:3]([OH:4])[CH:5]=[CH:6][C:7]=3[C:13]3([O:15][C:10](=[O:20])[C:11]4[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:5]=2[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: Cc1c(O)cccc1O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CCCCCCCCCCCC(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: Cc1c(O)ccc2c1Oc1c(ccc(O)c1C)C21OC(=O)c2ccccc21
Reaction time: 3 h

Procedure:
A mixture comprising 62 g of 2-methylresorcinol, 30 g of phthalic anhydride, 2 g of potassium hydrogen sulfate and 500 ml of ethyl laurate is brought to 200° C. for 3 hours. After cooling, the crude product is filtered and washed with acetone and then dried. The product obtained is a dark orange powder.
Reaction SMILES: [F:1][C:2]1([F:18])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][NH:14][C:13](=[O:17])[N:12]=3)[C:4]=2[O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].O>CN(C=O)C>[Cl:26][CH2:25][CH2:24][CH2:23][CH2:22][N:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:4]3[O:3][C:2]([F:1])([F:18])[O:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)=[N:12][C:13]1=[O:17]
Reactant: O=c1nc(-c2cccc3c2OC(F)(F)O3)cc[nH]1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2cccc3c2OC(F)(F)O3)ccn1CCCCCl
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-1H-pyrimidin-2-one (232 mg, 0.92 mmol) in dry DMF (18 ml), 60% NaH (47 mg, 1.19 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (137 μl 1.19 mmol) was added and the mixture was stirred overnight at room temperature. Water was added and the mixture extracted with diethyl ether. The organic layer was dried (Na2SO4) and evaporated. The residue purified by flash chromatography with hexane-ethyl acetate (8-2) to give 123 mg of the title compound (39% yield).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:14][C@@H:15]1[C@@:37]2([CH3:38])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[C@H:27]([CH3:32])[CH2:28][CH2:29][CH2:30][OH:31])[CH2:18][C@@H:17]([O:40][C:41](=[O:43])[CH3:42])[CH2:16]1)(=[O:13])[CH3:12].C(N(CC)CC)C>CCOCC.ClCCl>[C:11]([O:14][C@@H:15]1[C@@:37]2([CH3:38])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[C@H:27]([CH3:32])[CH2:28][CH2:29][CH:30]=[O:31])[CH2:18][C@@H:17]([O:40][C:41](=[O:43])[CH3:42])[CH2:16]1)(=[O:13])[CH3:12]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (0.27 ml; 3.81 mmol) was added at -78° C. in an argon atmosphere to 5 ml of a dichloromethane solution of 0.17 ml (1.95 mmol) of oxalyl chloride, and the mixture was stirred for 10 minutes under the same conditions. To the resulting solution was added 3 ml of a dichloromethane solution o 432 mg (0.94 mmol) of 1α,3β-diacetoxychol-5-en-24-ol (1), and the mixture was further stirred for 15 minutes. Triethylamine (1.05 ml; 7.55 mmol) was added to the reaction mixture, and the mixture was stirred for 5 minutes. The temperature of the reaction mixture was returned to ambient temperature. It was treated in a customary manner (extracted with ether). The crude product was purified by silica gel column chromatography [30 g; eluted with hexane/ethyl acetate (5:1)] to give 382 mg of the captioned aldehyde (2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[OH:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH2:22][CH2:21][CH2:20][OH:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: NCCCO
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Product: OCCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 3-hydroxypropan-1-amine to afford 3-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)propan-1-ol (Preparation Hv). LC-MS (M+H)+=322.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.08 (2 H, dd, J=8.55, 5.49 Hz), 6.97 (2 H, t, J=8.70 Hz), 5.18 (1 H, br. s.), 4.22-4.27 (1 H, m), 3.66-3.75 (4 H, m), 3.18 (1 H, br. s.), 2.60-2.77 (3 H, m), 2.02-2.12 (1 H, m), 1.78-1.86 (2 H, m)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([OH:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC1C=CC(Cl)=CC=1)=O)=N\C(OCC1C=CC(Cl)=CC=1)=O>ClCCl>[Si:11]([O:10][CH2:9][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1)[O:18][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[Cl:19])([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12]
Reactant: Oc1ccc(F)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccnc(N)n1
Agent: O=C(/N=N/C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(Oc1ccc(F)cc1Cl)c1ccnc(N)n1
Temperature: 45 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-2-(tert-butyldimethylsilyloxy)ethanol (19) (640 mg), 2-Chloro-4-fluorophenol (696 mg) and triphenylphosphine (1246 mg) in dichloromethane (10 mL) was added a solution of (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate in dichloromethane (20 mL) dropwise. The mixture was stirred at 45° C. overnight before being filtered and the filtrate was applied to a silica column and eluted with 10 to 100% ether in heptane. The product containing fractions were concentrated to afford the title compound (835 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1.FC1C=CC=CC=1C(Cl)=O.Br.BrCCN>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][CH2:10][CH2:11][N:12]=1
Reactant: Fc1ccccc1-c1ncco1
Agent: Br
Agent: NCCBr
Agent: O=C(Cl)c1ccccc1F
Product: Fc1ccccc1C1=NCCO1

Procedure:
Compounds of Formula 7 are commercially available or can be prepared by methods known to those of ordinary skill in the art. For example, a compound of Formula 7 in which L is fluoro, R1 is oxazol-2-yl and R2 is hydro (i.e., 2-fluoro-1-oxazol-2-ylbenzene) can be prepared by reacting 2-fluorobenzoic acid chloride with 2-bromoethylamine hydrobromide to give 2-fluoro-1-(4,5-dihydrooxazol-2-yl)benzene and then oxidizing. The reaction with the 2-bromoethylamine hydrobromide is carried out in the presence of a suitable base, typically a nitrogen base (e.g., triethylamine, N,N-diisopropylethylamine, etc., preferably triethylamine) and in a suitable solvent (e.g., benzene, methylene chloride, DMF, toluene, THF, any appropriate mixture of suitable solvents, etc., preferably benzene) at 50° to 110° C., typically at 100° to 110° C. and preferably at reflux, and requires 2 to 20 hours. The oxidation can be carried out with a suitable oxidizing agent (e.g., nickel peroxide hydrate, manganese dioxide, etc., preferably nickel peroxide hydrate) in a suitable solvent (e.g., benzene, methylene chloride, 1,2-dichloroethane, decalin, any appropriate mixture of suitable solvents, etc., preferably benzene) at 20° to 150° C., typically at 50° to 120° C. and preferably at reflux, and requires 2 to 40 hours. Further details of the process steps set forth in this paragraph are provide in Example 15, infra.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9](S(C)(=O)=O)[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=[O:4])=[O:3].C([Li])CCC.[OH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[CH3:1][S:2]([C:5]1[N:10]=[C:9]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=[O:3])=[O:4]
Reactant: Oc1ccccn1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Agent: [Li]CCCC
Product: CS(=O)(=O)c1nc(Oc2ccccn2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2,4-Bis(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Reference Example 5 (200 mg, 0.41 mmol) was reacted with 1.0 equivalent of n-butyl lithium and 1.1 equivalent of 2-hydroxypyridine by the procedure described in Example 86 to afford the title compound: 1H-NMR 400 MHz (CDCl3): δ 3.22 (s, 3H), 7.15-7.33 (m, 8H), 7.38 (d, J=2 Hz, 1H), 7.85-7.90 (m, 1H), 8.30-8.42 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][C:5]2=1.[F:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C([O-])([O-])=O.[Na+].[Na+].CO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:15]([C:13]1[CH:14]=[C:2]([C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([F:23])[CH:25]=2)[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][C:5]2=1)(=[O:17])[NH2:16]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(OC)c(F)c3)cc12
Temperature: 105 °C
Yield: 124.6 %

Procedure:
A 250 ml pressure flask was loaded with ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (1.39 g, 3.85 mmol, Example 58C), Pd(Ph3P)4 (280 mg, 0.242 mmol), 2-(3-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.30 g, 5.16 mmol), aqueous Na2CO3 (4.2 ml, 8.40 mmol), MeOH (21.00 ml) and Toluene (42 ml), flushed with nitrogen, sealed and heated to 105° C. for 4 hours in an oil bath. The reaction mixture was filtered and the collected solid washed with water. The filtrate was acidified with KHSO4 (1M solution in water) and extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4 and concentrated. The MgSO4 was washed with THF and a MeOH+CH2Cl2 mixture. All wash liquids, the extracted product and the collected solid residue were combined to give 1.95 g crude ethyl 8-carbamoyl-6-(3-fluoro-4-methoxyphenyl)-9H-carbazole-2-carboxylate. (estimated purity ˜75%). The crude product was used without further purification in the next reaction. MS (ESI) m/e−405 consistent with [M−H]− of product. HPLC retention time 2.13 min. (PHENOMENEX® Luna C18 S10, 3.0×50 mm column, 3 min gradient, 0-100% B, 4 mL/min. Solvent A: 5% CH3CN—95% H2O—10 mM NH4OAc; Solvent B: 95% CH3CN—5% H2O—10 mM NH4OAc), then isocratic at 100% B.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].Cl[C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[O:23])=[CH:20][NH:19][C:15]=2[N:16]=[CH:17][N:18]=1>>[CH3:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:1][C:13]2[C:14]3[C:21]([C:22](=[O:23])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[CH:20][NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:3]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Cc1ccccc1C(=O)c1c[nH]c2ncnc(Cl)c12
Product: CNC(=O)c1cccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4C)c23)c1

Procedure:
N-Methyl-3-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzamide was synthesized using 3-amino-N-methylbenzamide and ((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone according to the general procedure A. An off-white solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.47 (s, 1H), 8.48-8.47 (m, 2H), 8.24-8.20 (m, 2H), 7.60 (s, 1H), 7.52-7.45 (m, 4H), 7.40-7.32 (m, 2H), 2.86 (d, J=4.4 Hz, 3H), 2.34 (s, 3H); LCMS [M+H] 386.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]([C:19](=[O:36])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]2[CH:28]=[N:29][C:30]([C:34]#[N:35])=[CH:31][C:32]=2[CH3:33])[CH:21]=1)[CH3:18])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:17]([CH3:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:37])=[O:5])=[O:36])=[CH:21][C:22]=1[C:27]1[CH:28]=[N:29][C:30]([C:34]#[N:35])=[CH:31][C:32]=1[CH3:33]
Reactant: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2ccccc2OCCCC(=O)OC(C)(C)C)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2ccccc2OCCCC(=O)O)ccc1Cl

Procedure:
4-(2-{[4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric acid tert-butyl ester (60 mg, 0.12 mmol) was stirred in a mixture of DCM (400 μL) and TFA (400 μL) for 1 hr. The mixture was concentrated, dissolved in MeOH and purified by prep LCMS to yield 4-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric acid 5-1. MS [M+H]+: 463.7; tR=3.46 min, (method 2)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:8][N:9]1[C:13](I)=[C:12]([CH3:15])[N:11]=[C:10]1[CH2:16][CH2:17][CH3:18])=[O:7])[CH3:2].[Cu][C:24]#[N:25].N1C=CC=CC=1>ClCCl>[C:24]([C:13]1[N:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[O:3][CH2:1][CH3:2])[C:10]([CH2:16][CH2:17][CH3:18])=[N:11][C:12]=1[CH3:15])#[N:25]
Reactant: CCCc1nc(C)c(I)n1NC(=O)c1ccccc1OCC
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(C)c(C#N)n1NC(=O)c1ccccc1OCC
Temperature: 100 °C

Procedure:
2-Ethoxy-N-(5-iodo-4-methyl-2-propylimidazol-1-yl)benzamide from Example 1a (0.5 g, 1.2 mmol) and copper(I) cyanide (0.7 g, 7.5 mmol) are introduced into 10 ml of pyridine and heated at 100° C. for three hours. The reaction mixture is cooled to room temperature, 50 ml of dichloromethane are added, and the solid is removed by filtration. The filtrate is washed three times with 50 ml of water each time, and the organic phase is re-extracted with 50 ml of dichloromethane. The combined organic phase is dried with sodium sulphate and concentrated. To remove the remaining pyridine, the residue is taken up in 50 ml of dichloromethane and washed six times with 100 ml of water each time. The organic phase is dried with sodium sulphate and concentrated in a rotary evaporator. The residue is finally mixed with 100 ml of toluene and concentrated.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl>CCOC(C)=O>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)CN)C(=O)OCc1ccccc1
Reaction time: 1.33 h

Procedure:
To 9.0 g (20.6 mmoles) oily Boc-Gly-Val-OBzl (SEQ ID NO.14) were added 250 ml 2.6M HCl in EtOAc. The mixture was stirred for 80 min. and taken to dryness Under reduced pressure. Following repeated additions of EtoAc and evaporation to dryness under reduced pressure HCl, Gly-Val-OBzl (SEQ ID NO.9) was isolated as a white powder, Yield 5.6 g (79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[C:37]([F:39])[C:36]([S:40](=[O:59])(=[O:58])[N:41](CC3C=CC(OC)=CC=3OC)[C:42]3[S:46][N:45]=[CH:44][N:43]=3)=[CH:35][C:34]=2[F:60])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([N:16]([C:24](OC(C)(C)C)=O)[C:17](OC(C)(C)C)=O)[C:12]=3[CH:31]=2)[CH:7]=1.ClC1C=CC(OC2C(F)=CC(S(N(CC3C=CC(OC)=CC=3OC)C3SN=CN=3)(=O)=O)=C(F)C=2)=C(C2C=CC3ON=C(N(C)C)C=3C=2)C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[C:34]([F:60])=[CH:35][C:36]([S:40]([NH:41][C:42]3[S:46][N:45]=[CH:44][N:43]=3)(=[O:59])=[O:58])=[C:37]([F:39])[CH:38]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([N:16]([CH3:17])[CH3:24])[C:12]=3[CH:31]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Agent: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C)C)c4c3)cc2F)c(OC)c1
Product: CN(C)c1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cc12
Yield: 31 %

Procedure:
Following the procedure as described in EXAMPLE 44, making non-critical variations to replace di-tert-butyl [5-(5-chloro-2-{4-[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)sulfamoyl]-2,5-difluorophenoxy}phenyl)-1,2-benzoxazol-3-yl]imidodicarbonate with 4-(4-chloro-2-(3-(dimethylamino)benzo[d]isoxazol-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 4-(4-chloro-2-(3-(dimethylamino)benzo[d]isoxazol-5-yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide was obtained as a colorless solid in 31% yield (0.06 g): 1H NMR (300 MHz, DMSO-d6) δ8.53 (s, 1H), 8.03 (d, J=1.1 Hz, 1H), 7.74-7.68 (m, 2H), 7.66 (dd, J=8.7, 1.6 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.52 (dd, J=8.8, 2.7 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.13 (dd, J=10.5, 6.5 Hz, 1H), 3.08 (s, 6H); MS (ES+) m/z 563.6 (M+1), 565.6 (M+1).
Reaction SMILES: [CH2-]C(C)=O.[C:5]1([CH3:20])[CH:10]=[CH:9][C:8]([S:11]([O:14][CH2:15][CH:16]([OH:19])CO)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[Br:21][CH:22]1[CH2:30][CH2:29][C:28]2[N:27]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:26]=[CH:25][C:24]=2[C:23]1=[O:41].Cl.[OH-].[Na+]>O.C1C=CC=CC=1>[C:5]1([CH3:20])[CH:6]=[CH:7][C:8]([S:11]([O:14][CH:15]2[CH2:16][O:19][C:23]3([CH:22]([Br:21])[CH2:30][CH2:29][C:28]4[N:27]([S:31]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)(=[O:33])=[O:32])[CH:26]=[CH:25][C:24]3=4)[O:41]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CO)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C3=O)cc1
Agent: Cl
Agent: [CH2-]C(C)=O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)OC2COC3(O2)c2ccn(S(=O)(=O)c4ccc(C)cc4)c2CCC3Br)cc1
Yield: 42 %

Procedure:
A mixture of 3-p-toluenesulfonyloxypropyleneglycol acetonide (2 molar equivalents), 5-bromo-1-p-toluenesulfonyl-4-oxo-4,5,6,7-tetrahydroindole (100 parts), hydrochloric acid (1 molar equivalent) and benzene (500 to 2000 parts) is refluxed for 21 hours under azeotropic dehydration. After cooling, the reaction mixture is adjusted to pH 10 with 5N-sodium hydroxide, shaken and water layer drained. Organic layer is washed with water, (100 parts) and dried over anhydrous sodium sulfate (50 parts). The drying agent is removed by filtration. The filtrate is then concentrated under reduced pressure at a temperature below 50° C. to leave amorphous 4'-p-toluenesulfonyloxy-1-p-toluenesulfonyl-5-bromo-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]-dioxolane diastereomer mixture in 42% yield. The product is shown in Table I, Part 6, No. 18.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([S:42](=[O:45])(=[O:44])[NH2:43])[CH:37]=2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([S:42](=[O:44])(=[O:45])[NH2:43])[CH:37]=2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4cccc(S(N)(=O)=O)c4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2-c2cccc(S(N)(=O)=O)c2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.