Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:18][C@H:19]([OH:33])[CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:10]([OH:12])=[O:11].[O:44]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45]1>C(Cl)(Cl)Cl>[NH2:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH2:18][C@H:19]([O:33][CH:45]1[CH2:46][CH2:47][CH2:48][CH2:49][O:44]1)[CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:10]([OH:12])=[O:11]
Reactant: C1=COCCC1
Reactant: N[C@@H](CCCCN(C[C@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCN(C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1)C(=O)OCc1ccccc1)C(=O)O
Reaction time: 16 h
Yield: 51.9 %

Procedure:
Trifluoroacetic acid (164 mg, 1.44 mmol) was added to a solution of 17a (360 mg, 0.72 mmol) in CHCl3 (7 mL). The solution was concentrated in vacuo. The resultant oil was dissolved in CH2Cl2 (20 mL), and 3,4-dihydro-2H-pyran (69 mg, 75 μL, 0.83 mmol) was added at room temperature. The reaction progress was monitored by TLC, and six additional portions of 3,4-dihydro-2H-pyran (69 mg each) were added over the next 31 hours. The reaction mixture was stirred for an additional 16 hours and concentrated in vacuo. The oil was dissolved in water (4 mL) and methanol (8 mL), then adjusted to pH 7 with saturated NaHCO3 solution. The solution was concentrated, and the crude oil was purified by chromatography on a C-18 column (30% acetone/water, followed by 55% acetone/water) to give 18a (219 mg, 52%) as a colorless oil: 1H NMR δ 1.20-1.98 (m, 14H), 3.06-3.56 (m, 8H), 3.68-4.02 (m, 2H), 4.33-4.62 (m, 1H), 5.06 (s, 2H), 5.11 (s, 2H), 7.24-7.36 (m, 10H); 13C NMR δ 20.7, 21.1, 21.7, 23.6, 26.3, 26.5, 32.0, 32.5, 34.2, 38.1, 38.5, 52.0, 56.2, 64.2, 65.2, 67.3, 68.3, 74.9, 100.1, 101.6, 128.79, 128.96, 129.02, 129.10, 129.20, 129.47, 129.56, 129.62, 138.3, 138.5, 158.0, 158.7, 174.8; HRMS m/z calcd for C31H43N3NaO8 608.2948, found 608.2954.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=[O:13])=[O:5])C.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH2:14]([N:16]([CH2:17][CH3:18])[C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=[O:13])=[O:5])[CH3:15]
Reactant: CCNCC
Reactant: CCOC(=O)C1CC(C)CCC1=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)C1CC(C)CCC1=O
Yield: 65.1 %

Procedure:
5-Methyl-2-oxo-cyclohexanecarboxylic acid ethyl ester (45) (5.9 g, 32 mmol), DMAP (1.12 g, 10 mmol) and diethylamine (4.7 g, 65 mmol, 6.7 mL) in toluene (90 mL) were heated at reflux for 4 days. The reaction was allowed to cool and the toluene was removed under reduced pressure to give a yellow oil. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (20-50% B, 80 g) to afford 4.4 g (65%) of 5-methyl-2-oxo-cyclohexanecarboxylic acid diethylamide (46) as a yellow oil. The structure was confirmed 1H NMR (300 MHz, CDCl3) δH 0.8-1.05 (9H, m, CH3 and N(CH2CH3)2), 1.05-2.10 (5H, m, 5-CH and 4- and 6-CH2), 2.15-2.80 (2H, m, 3-CH2), 2.95-3.55 (5H, m, 1-CH and N(CH2CH3)2).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[CH2:14]=[O:15]>C(O)C>[OH:15][CH2:14][N:5]1[C:4](=[O:13])[C:3]2[C:9](=[CH:10][CH:11]=[CH:12][C:2]=2[CH3:1])[S:6]1(=[O:8])=[O:7]
Reactant: C=O
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Solvent: CCO
Product: Cc1cccc2c1C(=O)N(CO)S2(=O)=O
Temperature: 25 °C
Yield: 82 %

Procedure:
4-Methylsaccharin prepared in (b) (500 mg; 2.54 mmol) was dissolved in 2.53 ml of warm ethanol (steam bath). Once a homogeneous solution was achieved, formalin (37% in methanol; 1.76 ml excess) was added dropwise. The solution was allowed to cool to room temperature and then chilled to 0° C. for 4 days. The resulting solid was collected and air-dried to afford 476 mg (82%) of 2-hydroxymethyl-4-methylsaccharin, mp 196°-198° C. 1H nmr (300 MHz, CDCl3): 7.767 (1H, t, J=6.75 Hz); 7.732 (1H, d, J=7.72 Hz); 7.600 (1H, d, J=6.64 Hz); 5.361 (2H, d, J-8.00 Hz); 3.296 (1H, t, J=8.16 Hz); 2.793 (3H, s). IR (KBr, cm1): 3505 (s); 3070 (w); 1735 (s); 1580 (m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:43])[C:32]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38](O)[CH:37]=1)([CH3:34])[CH3:33])[CH3:29].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:28]([O:30][C:31](=[O:43])[C:32]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:37]=1)([CH3:34])[CH3:33])[CH3:29]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)C(C)(C)Oc1cccc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1cccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), 2-(3-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (CAS RN: 328919-24-0), tri-n-butylphosphin and N,N,N′,N′-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow solid (19%). MS (Turbo Spray): m/z=597.2 [M+H].
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH:18]=[CH:19][C:20]([F:32])([F:31])[O:21][C:22]3[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]>C1(C)C=CC=CC=1.C(O)C.[C].[Pd]>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]([F:32])([F:31])[O:21][C:22]3[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=3)[CH2:14][CH2:13]2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=CC(F)(F)Oc3cc(F)c(F)c(F)c3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC(F)(F)Oc3cc(F)c(F)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In a nitrogen-purged 1-L stainless steel autoclave, 7.7 g (16.8 mmol) of 1-(3-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl)-1,1-difluoro-2-propenyloxy)-3,4,5-trifluorobenzene obtained in Example 3 was dissolved in 200 ml of a mixed solution of equal amount of toluene/ethanol. 0.8 g of 5% palladium carbon catalyst was added thereto, and the mixture was stirred at room temperature under a hydrogen pressure of 0.1 to 0.2 MPa for 10 hours. The catalyst was separated from the reaction mixture by filtration, and then the solvent was distilled off under reduced pressure. The concentrated residue was purified by means of a silica gel column chromatography with heptane as a developing solvent and further recrystallized from a mixed solution of equal amount of heptane/ethanol to obtain 4.9 g of 1-(3-(trans-4-(trans-4-pentylcyclohexyl)-cyclohexyl)-1,1-difluoropropoxy)-3,4,5-trifluorobenzene as colorless crystals.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1>>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)=[O:15])(=[O:8])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 71 but using 3-(piperidin-1-ylsulfonyl)benzoic acid (100 mg) and 4-aminobenzotrifluoride (59 mg) as the starting materials.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:1]2[CH:5]=[N:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[N:2]2)[CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(-c2nc[nH]n2)nc1
Reactant: Fc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(-n2cnc(-c3ccccn3)n2)c1
Temperature: 100 °C

Procedure:
2-(1H-1,2,4-Triazol-3-yl)pyridine (1.0 g, 6.8 mmol), potassium carbonate (1.88 g, 13.6 mmol) and 1-chloro-3-fluorobenzene (0.89 g, 6.8 mmol) were stirred in DMF (20 mL) at ambient temperature. The resulting reaction mixture was heated at 100° C. for 16 h, after which time it was quenched with H2O (50 mL) and diluted with EtOAc (200 mL). The EtOAc solution was washed with H2O (3×100 mL), then brine (100 mL) and dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexanes: EtOAc (40:60) to afford 2-[1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl]pyridine as a white solid which was then dissolved in dichloromethane (5 mL) and precipitated as the hydrochloride salt (M.p.=221–223° C.) upon treatment with 1M HCl in diethyl ether (5 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[C:12]([NH:13][C:14](=O)CBr)=[C:11]([CH3:18])[O:10][N:9]=2)=O)=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:25](=[O:28])(O)[O-].[Na+].[CH3:30][N:31](C)C=O>CCCCCC>[CH3:18][C:11]1[O:10][NH:9][C:8]2[C:12]=1[N:13]([CH3:14])[C:25](=[O:28])[CH:30]=[N:31][C:6]=2[C:5]1[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])O
Reactant: Cc1onc(C(=O)c2ccc(Cl)cc2)c1NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Product: CC1=C2C(=C(c3ccc(Cl)cc3)N=CC(=O)N2C)NO1
Temperature: 20 °C

Procedure:
A solution of N-[3-(4-chlorobenzoyl)-5-methylisoxazol-4-yl]-bromoacetamide of Example Vc (4.26 g, 15.5 mmoles) in dimethylformamide (DMF) (40 ml) was added to a suspension of hexane-washed sodium hydride (0.67 g, 14 mmoles, 50% oil dispersion) in DMF (40 ml) at 5° C. After warming to 20° C., methyl iodide (1.06 ml, 17 mmoles) was added. The reaction solution was Poured into dilute sodium bicarbonate (600 ml) with stirring. The precipitate was extracted with ethyl acetate, the organic solution was washed with water, saturated sodium chloride, and dried (sodium sulfate). Concentration gave a residue (5.5 g) which was chromatographed by high pressure liquid chromatography (HPLC) (8% ethyl acetate:dichloromethane) to give a solid that was pulverized to yield 3.0 g (66%) of a powder, melting point 133°-145° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([NH:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:24]1[CH2:25][CH2:26][CH2:27][C@@H:22]([NH:21][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[C:11]([C:9]4[NH:10][C:6]5[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=5[CH:8]=4)[CH:12]=[CH:13][CH:14]=3)[N:19]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(N[C@@H]5CCCNC5)nc34)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
A mixture of (R)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)amino)piperidine-1-carboxylate (78.0 mg, 0.169 mmol) and TFA (0.45 mL, 5.84 mmol) in DCM (1.5 mL) was stirred at 0° C. for 10 min, then at 25° C. for 1 h. The mixture was concentrated in vacuo, and the residue was taken up in DMSO (2.0 mL) and purified by reversed-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) to provide (R)-2-(2-(piperidin-3-ylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (30.7 mg, 0.065 mmol, 38% yield) as a yellowish-brown solid: 1H NMR (400 MHz, MeOH-d4) δ ppm 8.08 (1H, dd, J=9.6, 4.1 Hz), 7.85 (1H, dd, J=7.5, 1.3 Hz), 7.65 (1H, d, J=7.4 Hz), 7.43 (1H, br. s.), 7.37 (1H, t, J=7.5 Hz), 6.96 (1H, d, J=7.2 Hz), 4.40-4.50 (1H, m), 3.79 (1H, dd, J=11.7, 2.3 Hz), 3.66 (2H, t, J=7.0 Hz), 3.43 (1H, dt, J=12.8, 4.3 Hz), 3.06-3.18 (2H, m), 3.03 (2H, t, J=7.1 Hz), 2.27-2.38 (1H, m), 2.10-2.22 (1H, m), 1.93-2.07 (1H, m), 1.72-1.85 (1H, m). 19F NMR (377 MHz, MeOH-d4) δ ppm −77.29 (3F, s). m/z (ESI, +ve) 362.1 (M+H)+.
Reaction SMILES: N=C=N.[CH3:4][N:5]([C:9]1[S:10][CH:11]=[N:12][N:13]=1)[CH2:6][CH2:7][NH2:8].[Cl:14][C:15]1[CH:16]=[C:17]([C:21]#[C:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([C:21]#[C:22][C:23]([NH:8][CH2:7][CH2:6][N:5]([CH3:4])[C:9]2[S:10][CH:11]=[N:12][N:13]=2)=[O:24])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)C#Cc1cccc(Cl)c1
Reactant: CN(CCN)c1nncs1
Agent: N=C=N
Solvent: ClCCl
Product: CN(CCNC(=O)C#Cc1cccc(Cl)c1)c1nncs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
3.25 g (≅4.0 mmol) PS carbodiimide was added to a solution of 317 mg (2.0 mmol) N1-methyl-N1-(1,3,4-thiadiazol-2-yl)ethane-1,2-diamine and 542 mg (3.0 mmol) 3-(3-chloro-phenyl)propiolic acid in DCM (20 ml) and the reaction solution was shaken for 16 h at RT. The resin was subsequently filtered off, washed with DCM and ethanol and the filtrate concentrated in a vacuum. CC (chloroform) was performed with the residue, whereby 165 mg (0.51 mmol, 26%) 3-(3-chlorophenyl)-N-(2-(methyl(1,3,4-thiadiazol-2-yl)amino)ethyl)propiolamide was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=[CH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].[BH3-]C#N.[Na+]>CO.CC(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=CCCC(=O)O
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCCC(=O)O
Reaction time: 0.33 h
Yield: 30.1 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (350 mg, 0.93 mmol, 1 eq) in anhydrous methanol (6.5 mL) and AcOH (65 μL) was added 4-oxobutanoic acid (15% in water, 710 mg, 1.0 mmol) at room temperature. After 20 min of stirring, NaBH3CN (130 mg, 2.0 mmol) was added in one portion and the reaction mixture was stirred for another 4 h at room temperature. The reaction mixture was quenched by addition of AcOH (0.5 mL) at 0° C. and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (5-75% ethyl acetate/hexanes) to give 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butylindolin-1-yl)butanoic acid (130 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]#N.S(=O)(=O)(O)[OH:14].[OH2:18]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]([OH:14])=[O:18]
Reactant: O
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: O=S(=O)(O)O
Product: Cc1cc(C)c(CC(=O)O)c(C)c1
Temperature: 50 °C

Procedure:
155 g (2,4,6-trimethylphenyl)acetonitrile are added to a solution of 1.1 L of water and 915 mL of concentrated sulfuric acid heated to 50° C. The mixture is refluxed for 6 hours with stirring. Then the reaction mixture is poured onto 3 kg of ice. The solid is suction filtered and washed with water. Yield: 131 g (86%); melting point: 163° C.-166° C.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][O:28][CH3:29].O>C(#N)C>[CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][N:14]([CH2:26][CH2:27][O:28][CH3:29])[N:13]=2)=[CH:8][CH:7]=1)([CH3:2])[CH3:4]
Reactant: COCCBr
Reactant: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCn1cc(C=O)c(-c2ccc(OC(C)C)cc2)n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A mixture of 3-[4-(propan-2-yloxy)phenyl]-1H-pyrazole-4-carbaldehyde hydrochloride (400 mg, 1.5 mmol) and K2CO3 (655 mg, 4.6 mmol) in acetonitrile (6 ml) was stirred at 0-5° C. for 1 hr. 1-bromo-2-methoxyethane (195 mg, 1.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 48 h. The reaction was poured into water (200 mL) and extracted with EtOAc (50 mL×3). The combined extracts was washed with brine (100 mL), dried and concentrated under vacuum (360 mg, yield 72%). The crude material was used in the next step without purification.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6](Cl)[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[CH2:2][CH3:3].O.[NH2:28][NH2:29]>C(O)C>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:28][NH2:29])[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[CH2:2][CH3:3]
Reactant: NN
Reactant: CCCc1nc(C)nc(Cl)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCO
Solvent: O
Product: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
51.7 g of 6-n-propyl-2-methyl-4-chloro-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 10, are dissolved in 150 ml of ethanol and 90 ml of hydrazine hydrate. The mixture is heated to reflux for 6 hours and the solvent is concentrated to one half under vacuum and then treated with water. The crystals formed are drained, washed with water and then with ether and dried to give 46 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine in the form of crystals of melting point 156° C.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([CH:16]([CH3:19])[CH:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:20][C:21]([CH:23]=[CH:24][CH3:25])=[CH2:22]>C1(C)C=CC=CC=1>[CH3:20][C:21]1[CH2:22][CH:17]([CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:19])[O:18][CH:24]([CH3:25])[CH:23]=1
Reactant: C=C(C)C=CC
Reactant: CC(C=O)c1ccccc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1=CC(C)OC(C(C)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
A 5-L reaction flask equipped with a reflux condenser was charged with toluene (1 L) and borontrifluride etherate (C4H10BF3O) (16 g, 0.012 mol). The reaction flask was cooled to 0° C. and 2-phenylpropanal (300 g, 2.23 mol) was added over 15 minutes. 2-Methyl-1,3-pentadiene (1.22 Kg, 4.92 mol) was added over 1 hour. During the feed, the reaction exothermed to 10° C. The reaction mixture was aged overnight and then quenched with aqueous sodium hydroxide (50%, 1 L). Vacuum distillation of the resulting mixture afforded 4,6-dimethyl-2-(1-phenyl-ethyl)-3,6-dihydro-2H-pyran (120 g) having a boiling point of 118-120° C. at 3 mmHg.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)[CH:23]=2)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13]CC)=[O:12])[CH:7]=1.FC1C(C2C=CC(N3N=CC=N3)=CC=2)=CC(=O)N(CC[C@@](C)(S(C)(=O)=O)C(O)=O)C=1>>[F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)[CH:23]=2)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([OH:13])=[O:12])[CH:7]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)S(C)(=O)=O
Agent: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)O)S(C)(=O)=O
Product: C[C@@](CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)(C(=O)O)S(C)(=O)=O
Yield: 28.3 %

Procedure:
The title compound (144 mg, 28.4%) was prepared as an off-white solid from ethyl (2R)-4-{5-fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate (538 mg, 1.09 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoic acid, Example 26, Step C. MS (LCMS) m/z 467.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 2.12-2.27 (m, 1H) 3.17 (s, 3H) 3.85-4.11 (m, 2H) 6.55 (d, J=7.61 Hz, 1H) 7.24-7.35 (m, 2H) 7.44-7.66 (m, 4H) 8.07 (d, J=6.44 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:6]=1)=[O:4].[CH2:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[S:19])[CH3:16]>C(OC(C)C)(C)C>[ClH:1].[CH2:21]([N:20]1[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:6]=2)([OH:4])[CH2:2][S:19][C:18]1=[N:17][CH2:15][CH3:16])[CH3:22]
Reactant: CCNC(=S)NCC
Reactant: NS(=O)(=O)c1cccc(C(=O)CCl)c1
Solvent: CC(C)OC(C)C
Product: CCN=C1SCC(O)(c2cccc(S(N)(=O)=O)c2)N1CC
Product: Cl

Procedure:
3.5 g of 2-chloro-3'-sulfamoylacetophenone and 2.1 g of ground 1,3-diethylthiourea were reacted as prescribed in Example 12. 150 ml of diisopropyl ether were added, the solvent was decanted and the amorphous end product was crystallized under ethyl acetate. Colorless solid body, decomposition beginning at 80° C., γ C=N 1615 cm-1.
Reaction SMILES: C([C@H]([C@@H](C(OC(C)C)=O)O)O)(OC(C)C)=[O:2].C(OO)(C)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[CH2:32][OH:33])=[CH:26][C:25]=1[F:34]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C@H:30]2[O:2][C@@H:31]2[CH2:32][OH:33])=[CH:26][C:25]=1[F:34]
Reactant: CC(C)OC(=O)[C@@H](O)[C@H](O)C(=O)OC(C)C
Reactant: OC/C=C/c1ccc(Cl)c(F)c1
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Product: OC[C@H]1O[C@@H]1c1ccc(Cl)c(F)c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 647.8 %

Procedure:
Diisopropyl D-tartrate (1.690 mL, 8.038 mmol) was dissolved in dichloromethane (500 mL) and cooled to −20° C. Activated powdered 4 Å molecular sieves (3 g), titanium(IV) isopropoxide (1.570 mL, 5.359 mmol) and tert-butyl hydroperoxide (19.49 mL, 107.2 mmol; in decane) were added sequentially, and the mixture was agitated for 1 hour at −20° C. (E)-3-(4-Chloro-3-fluorophenyl)prop-2-en-1-ol (10.0 g, 53.59 mmol) was dissolved in dichloromethane (25 mL) and treated with 4 Å molecular sieves (1.0 g) for 1 hour. This mixture was added to the initial mixture over 20 minutes and agitation was continued for another 3 hours at −20° C. The reaction was then quenched by addition of a mixture of a saturated NaCl solution (3 mL) and 50% w/v NaOH (3 mL). Ether was added (100 mL), and the mixture was allowed to warm up to 10° C. After agitating for 10 minutes at this temperature, MsSO4 (5 g) and Celite® (2 g) were added, and the mixture was agitated for an additional 15 minutes. The mixture was then allowed to settle and filtered through a pad of Celite®, washing with ether. Solvents were then evaporated, and resulting solid was triturated with hexane to give ((2R,3R)-3-(4-chloro-3-fluorophenyl)oxiran-2-yl)methanol (10.55 g, 52.07 mmol, 97.17% yield) as a solid.