Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].C(O)CCC.[CH2:35](Br)[CH2:36][CH2:37][CH2:38][CH3:39]>O>[CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc2nc(-c3ccc(O)cc3)ccc2c1
Reactant: CCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCc1ccc2nc(-c3ccc(OCCCCC)cc3)ccc2c1
Yield: 83.8 %

Procedure:
To a solution 0.8 g of 6-decyl-2-(4-hydroxyphenyl)quinoline and 170 mg potassium hydroxide in i2 ml of butanol, 0.5 g of pentyl bromide was added, followed by heat refluxing for 4 hours. After the reaction, the reaction mixture was poured into water and subjected to extraction with toluene. The organic layer was washed with water, dried with anhydrous sodium sulfate and subjected to distilling-off of the solvent, followed by purification by silica gel column chromatography and recrystallization to obtain 0.8 g of 6-decyl-2-(4-pentyloxyphenyl)quinoline. This compound showed the following phase transition series.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[CH2:33][C@H:32]([CH3:34])[NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:14])[F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[CH2:33][C@H:32]([CH3:34])[N:31]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CN[C@@H](C)C1
Agent: Cl
Product: COCC(=O)N1C[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-[(3S*,5S*)-5-methylpyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f66) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:4]=1.[N:38]1([CH2:44][CH2:45][O:46][CH2:47][CH2:48][OH:49])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C1COCC1.CCOC(C)=O>[OH:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][N:38]1[CH2:43][CH2:42][N:41]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]3[CH:17]=[C:16]([C:18]#[C:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]5[O:30][CH:31]=[CH:32][C:33]=5[CH3:34])=[O:28])[CH:21]=4)[CH:15]=[N:14][CH:13]=3)=[CH:5][CH:4]=2)[CH2:40][CH2:39]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CBr)cc3)c2)c1
Reactant: OCCOCCN1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CN4CCN(CCOCCO)CC4)cc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Crude N-{[4-(Bromomethyl)phenyl] (methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide was dissolved in THF (2 mL). 2-(2-piperazin-1-yl-ethoxy)-ethanol (0.064 g, 0.390 mmol) and TEA (0.054 mL, 0.390 mmol) were then added to the solution and the resulting reaction mixture was allowed to stir for 1 h at rt. The reaction mixture, subsequently, was dissolved in EtOAc and then extracted with H2O (2× mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 20% MeOH) to afford the title compound (0.064 g, 49% overall for step 1 and 2).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:40][CH2:41][CH:42]1[CH2:46][NH:45][CH2:44][CH:43]1[OH:47].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[NH2:40][CH2:41][CH:42]1[CH:43]([OH:47])[CH2:44][N:45]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([Cl:28])([F:26])[F:27])=[CH:22][CH:23]=3)=[O:16])=[CH:4][N:3]=2)[CH2:46]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Reactant: NCC1CNCC1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: NCC1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncc(F)c2)CC1O
Temperature: 80 °C
Reaction time: 72 h

Procedure:
2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide (Stage 266.1, 80 mg, 0.183 mmol) and DIPEA (0.224 mL, 1.282 mmol) were added to a vial containing iPrOH (2 mL) and 4-(aminomethyl)pyrrolidin-3-ol dihydrochloride (Stage 267.1, 37.1 mg, 0.192 mmol) was added under an argon atmosphere. The RM was stirred at 80° C. for 3 days. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure to give the crude product was purified by preparative HPLC (Condition 14). Fractions containing product were treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The resulting aq. residue was extracted with EtOAc and the combined extracts were dried over Na2SO4, filtered and evaporated. The residue was suspended in DCM/Et2O/n-hexane. The obtained solid was filtered off, washed with Et2O, n-hexane and dried to afford the title product as a white solid. HPLC (Condition 10) tR=5.74 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=508 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.41-3.33 (m, 7H) 3.92-4.21 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.85 (d, J=9.38 Hz, 3H) 8.03-8.11 (m, 1H) 8.47-8.54 (m, 1H) 8.59 (m, J=2.70 Hz, 1H) 8.77 (m, J=2.30 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([F:13])[CH:12]=1)C=O)([CH3:4])([CH3:3])[CH3:2].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(N(CC)CC)C.[CH:32](OC)([O:35][CH3:36])[O:33][CH3:34]>CO>[C:1]([C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[C:7]([CH:32]([O:35][CH3:36])[O:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)cc(C=O)c1
Reactant: COC(OC)OC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(OC)c1cc(F)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
3-tert-Butyl-5-fluoro-benzaldehyde (252 g, 1.4 moles) was dissolved in methanol (4 vol, 1000 ml) and trimethyl orthoformate (1 vol, 252 ml). Toluenesulfonic acid (3.4% w/w, 6 g) was added in one portion and the resulting solution stirred at rt for 1 hour. Triethylamine (0.12 vol, 30 mL) was added and the reaction concentrated to an oil, and then re-suspended in ethyl acetate (3 L) and NaHCO3 (aq. sat., 1 L) and water (1 L) with vigorous mixing. The organic phase was washed with additional water (1 L), polish filtered and then concentrated to provide an orange oil (311.2 g, 98.5%), used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13](C)C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.Cl.[C:21]([NH:25]N)([CH3:24])([CH3:23])[CH3:22].C(O)C>O>[C:21]([N:25]1[C:4]([C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[Cl:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[N:13]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(C(C)(C)C)c1-c1ccccc1Cl
Temperature: 25 °C
Yield: 15.6 %

Procedure:
A mixture of 2.82 g of ethyl 2-(2-chlorobenzoyl)-3-(N,N-dimethylamino)acrylate (a compound described in JP-A 7-101940), 1.25 g of tert-butylhydrazine hydrochloride and 10 ml of ethanol was heated to reflux for 8 hours. After the reaction mixture was allowed to cool to room temperature, water was poured and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.48 g of ethyl 1-tert-butyl-5-(2-chlorophenyl)-1H-pyrazole-4-carboxylate of the formula:
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17]>>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CCC(=O)NC1CCc2c(-c3ccc(C#N)cc3)cncc21
Yield: 79 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-4) was reacted with 4-cyanophenylboronic acid to give the title compound as light green powder in 79% yield. MS: 292.1 (M+H+).
Reaction SMILES: [C:1]([C:4](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:5]([O:7]CCC#N)=[O:6])(=O)[CH3:2].[NH2:22]/[C:23](/[CH3:49])=[CH:24]\[C:25]([O:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][C:34]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)=[O:26].C(O)(=O)C>CC(O)C>[C:43]1([C:34]2([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH2:28][O:27][C:25]([C:24]3[CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=4)[C:4]([C:5]([OH:7])=[O:6])=[C:1]([CH3:2])[NH:22][C:23]=3[CH3:49])=[O:26])[CH2:36][CH2:35]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCC#N
Reactant: C/C(N)=C/C(=O)OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)=C(C)N1

Procedure:
8.1 g of 2-cyanoethyl 2-acetyl-3-(3-nitrophenyl)acrylate and 10.6 g of 3-(4,4-diphenylpiperid-1-yl)-propyl 3-aminocrotonate are heated at the boiling point under reflux in 120 ml of 2-propanol and 0.5 ml of glacial acetic acid for 4 hours. After most of the solvent has been distilled off and 2 portions of 50 ml of toluene each have been added, the residue is concentrated to dryness. The residue, which has foamed as a solid, is taken up in isopropanol, and diethyl ether is added to the clear solution until the resulting cloudiness first persists. After the mixture has been left to stand in a refrigerator, the starting compound crystallizes out in the form of fine platelets. m.p.: 158°-160° C.; yield: 14.3 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:11][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Temperature: 90 °C

Procedure:
157 g (1.00 mol) of 3-fluoro-6-nitrophenol are initially taken in 500 ml of acetonitrile in a three-necked flask (KPG stirrer, reflux condenser, inert gas connection), and 174 g (1.02 mol) of benzyl bromide and 345 g (2.50 mol) of potassium carbonate are added in this sequence under inert gas. The mixture is refluxed for 3 hours at 90° C. After cooling to room temperature, the mixture is filtered with suction and the remaining solid is rinsed twice with 100 ml of acetonitrile each time. The solution is evaporated down until it crystallizes, and the crude product is filtered off with suction. The crude product is dissolved at room temperature in ethyl acetate (1 ml/g of crude product) and precipitated with hexane (3.6 ml/g of crude product). The mixture is stored overnight at T<−10° C. for complete crystallization.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.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>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=4)[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.575 g, 0.76 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.227 g, 0.85 mmol), tetrakis(triphenylphosphine)palladium (0.051 g, 0.038 mmol) in toluene (5 mL) was heated under reflux conditions for 4 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), placed in freezer for 30 min, added heptane (total volume: 25 mL), filtered the precipitate off, washed with toluene/heptane (ca. 1:1, 3×10 mL), dried in HV to give the title compound as an off-white solid (305 mg, 70%). MS (ISP) 576.3 [(M+H)+]; mp 236° C.
Reaction SMILES: [Li]OC(C)=O.O.O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15](C(O)=O)=[CH:14][C:13]=2[CH:21]=1.C1C(=O)N([Br:29])C(=O)C1>CC#N.O>[Br:29][C:15]1[CH2:16][O:17][C:12]2[C:13]([CH:14]=1)=[CH:21][C:9]([Cl:8])=[CH:10][CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2OC1
Agent: [Li]OC(C)=O
Solvent: CC#N
Solvent: O
Product: Clc1ccc2c(c1)C=C(Br)CO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.6 %

Procedure:
To a solution of LiOAc.2H2O (0.16 g, 1.62 mmol) in 97:3 CH3CN/H2O (30 mL) was added 6-chloro-2H-1-benzopyran-3-carboxylic acid (1.43 g, 8.12 mmol), followed by NBS (1.52 g, 8.53 mmol) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then concentrated to dryness under reduced pressure. Purification by flash column chromatography (gradient, hexanes, then 98:2 to 90:10 hexanes/Et2O) gave 3-bromo-6-chloro-2H-chromene (0.47 g, 27%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.14-7.10 (m, 1H), 6.94-6.88 (m, 2H), 6.79 (d, J=8.1 Hz, 1H), 6.75 (s, 1H), 4.88 (d, J=1.5 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=2.Cl.[CH3:32][NH:33][CH3:34].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[CH3:32][N:33]([CH3:34])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH2:21][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:23]=1
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)O)c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.2 %

Procedure:
A solution of 60 mg (0.139 mmol) of 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzoic acid (example 31) in 1 mL of THF was treated with 31 mg (0.417 mmol) of dimethylamine hydrochloride, 0.09 mL (0.834 mmol) of N-methylmorpholine, 3.7 mg (0.028 mmol) of HOBT, and 37 mg (0.195 mmol) of EDCI. The mixture was stirred for 10 hrs at RT and the solvent evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 to 1:1 yielded 39 mg (60%) of N,N-dimethyl-3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzamide, colorless solid, MS: 459 (MH+).
Reaction SMILES: [C:1]([N:4]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:11]=[C:10]([CH3:25])[C:9]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>ClCCCl>[C:1]([N:4]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[N+:11]([O-:39])=[C:10]([CH3:25])[C:9]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3)c2c1N(C(C)=O)C(C)=O
Solvent: ClCCCl
Product: CCOC(=O)c1c(N(C(C)=O)C(C)=O)c2c(OC3CCCCC3)cccc2[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 4-(N-acetylacetamido)-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (Example 132b, 100 mg, 0.24 mmol) in DCE (5 mL) was added mCPBA (163 mg, 0.73 mmol). The reaction mixture was stirred at room temperature overnight under N2. The solvent was removed under reduce pressure, and the residue was purified by chromatography on silica gel eluting with 0-100% EtOAc/Hexanes gradient to give the title compound as an orange oil (100 mg, 97%). MS 429 (MH+).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:36])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])[CH2:19][CH2:18]3)[N:14]=2)[CH2:7]1)(=O)=O.[C:37]([O-:40])(=[S:39])[CH3:38].[K+]>CN(C)C=O>[C:37]([S:39][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:36])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])[CH2:19][CH2:18]3)[N:14]=2)[CH2:9]1)(=[O:40])[CH3:38]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)NC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)NC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (390 mg, 0.723 mmol) (obtained as described in Reference Example 51(7)) in dimethylformamide (20 ml) was added potassium thioacetate (496 mg, 4.34 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate as the eluant to afford 3-acetylthio-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (262 mg, yield 70%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31]>O>[CH3:1][O:2][C:3]([CH2:4][N:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:29][C:30]([OH:32])=[O:31])[C:6]1=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)CN1Cc2ccccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1Cc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid methyl ester (9.5 g, 29.3 mmol) and K2CO3 (2.5 eq, 10.31 g, 73.3 mmol) in a round bottom flask are treated with dry DMF. Tert-Butyl bromoacetate (1.02 eq, 4.2 ml, 30 mmol) is added dropwise via syringe under argon. The reaction suspension is stirred at RT for one hour. The reaction mixture is diluted with distilled water and extracted with EtOAc (3×). The separated organic layer is dried over MgSO4, filtered and the solvent concentrated in vacuo. The title compound is obtained as brown viscous oil crystallizing on standing. [M+H]+ 335.
Reaction SMILES: C([CH:3]([C:32]([OH:34])=[O:33])[N:4]([CH2:15][P:16]([S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[CH2:36](OCC)C>C(O)(=O)C>[CH2:5]([N:4]([CH2:15][P:16]([S:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([S:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[S:17])[CH2:3][C:32]([OH:34])=[O:33])[CH3:36]
Reactant: CCOCC
Reactant: CCC(C(=O)O)N(CP(=S)(Sc1ccccc1)Sc1ccccc1)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(Sc1ccccc1)Sc1ccccc1

Procedure:
Ethyl-N-[bis(phenylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (2.3 g.) was dissolved in 10 ml. of 35% hydrobromic acid in acetic acid and stirred for approximately one hour. Diethyl ether was added to precipitate the hydrobromide salt of the desired compound. The hydrobromide salt was washed an additional three times with diethyl ether. The oily residue was then dissolved in benzene and treated with excess propylene oxide and the resulting solution concentrated in vacuo to yield ethyl-N-[bis(phenylthio)phosphinothioylmethyl]-glycine as an oil, ND25 =1.413.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].O1CCOCC1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O>[C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)#[N:2]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1I
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Temperature: 90 °C
Yield: 81.7 %

Procedure:
To a 500 mL RBF containing ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (17.20 g, 44.65 mmol, prepared as in WO 2009154741) was added anhydrous 1,4-dioxane (172.0 mL, 2204 mmol). To the resulting suspension was added morpholine (8.177 mL, 93.77 mmol). A reflux condenser was attached and the pink/orange heterogeneous suspension was heated to bath temp 90° C. and allowed to stir. Shortly after heating began, reaction mixture became a cherry red, homogenous solution. Reaction was stirred for 16 hours at 90° C. The reaction was then cooled to room temperature and diluted with water (100 mL). Mixture was filtered, and the solid was dried for in vacuo at 40° C. for 5 days to afford ethyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (14.3 grams, 82% yield). LCMS: (FA) ES+ 393; 1H NMR (400 MHz, DMSO) δ 4.24 (q, J=7.1, 2H), 3.78-3.70 (m, 4H), 3.63-3.57 (m, 4H), 1.26 (t, J=7.1, 3H).