Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:10][CH2:11][O:12][C:13]([CH2:15][NH:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=2[Cl:26])[N:19](C(OC(C)(C)C)=O)[C:18]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:14])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([CH2:10][CH2:11][O:12][C:13]([CH2:15][NH:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=2[Cl:26])[NH:19][C:18]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:14])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCC(=O)OCCCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)OCCCC(=O)c1ccccc1
Reaction time: 3.5 h
Yield: 82.6 %

Procedure:
Dissolve 3-[(phenacyl)carbethoxymethyl-amino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (0.4 g, 0.71 mmol) in methylene chloride (6 mL) and add, by dropwise addition, trifluoroacetic acid (6 mL). Stir for 3.5 hours and pour slowly into saturated sodium hydrogen carbonate (100 mL). Extract with ethyl acetate and dry (MgSO4). Evaporate the solvent in vacuo and recrystallize the residue (ethyl acetate/hexane) to give the title compound (0.28 g, 85%); mp 139°-40° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Br:29])[CH:16]=1)[C:10]([O:12]C)=[O:11].C(N(CC)CC)C.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[Li+].Cl>CO.O>[Br:29][C:17]1[CH:16]=[C:15]([CH2:14][C@@H:9]([NH:8][S:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:45])=[O:44])[C:10]([OH:12])=[O:11])[CH:20]=[CH:19][C:18]=1[CH:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1CC(c2ccc(C[C@@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
Methyl (2S)-2-amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-phenyl]-propanoate trifluoroacetate (77.1 mg, 0.152 mmol) in methanol (1.7 mL,) was treated with triethylamine (85.0 μL, 0.610 mmol) and then benzenesulfonyl chloride (29.2 μL, 0.228 mmol). The solution was stirred at rt for 2 h. 4 M lithium hydroxide in water (0.38 mL) was added and stirred for 3 h at rt. The solution was acidified with aqueous 1 N hydrochloric acid solution (4 mL), diluted with methanol (1.5 mL) and purified by preparative LCMS to afford product as a white solid (55.4 mg, 70%). 1H NMR (400 MHz, CD3OD): δ 7.65–7.62 (m, 2H), 7.53–7.36 (m, 4H), 7.25–7.20 (m, 1H), 5.65 (t, J=6.8 Hz, 1H), 4.06–5.01 (m, 1H), 3.48 (dd, J=16.2, 8.0 Hz, 1H), 3.38–3.28 (m, 1H), 3.11–3.06 (m, 1H), 2.87–2.83 (m, 1H); LCMS found for C18H18BrN2O7S2 (M+H)+: m/z=517.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:38])[CH2:6][CH2:7][CH2:8][N:9]([CH2:11][C@H:12]([O:14][C:15]1[C:16]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=3)=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:21][C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:13])[CH3:10].Cl>O1CCOCC1>[CH2:30]([C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:16]3[C:15]([O:14][C@H:12]([CH3:13])[CH2:11][N:9]([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]([OH:38])=[O:4])=[N:20][CH:19]=[N:18][C:17]=3[O:21][C:22]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:29][CH:28]=1)[CH3:31]
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)CN(C)CCCC(=O)OC)c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)CN(C)CCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add 0.6 ml 1 N sodium hydroxide solution to a solution of 100 mg (73% purity, 0.15 mmol) 4-{[(2R)-2-{[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}propyl](methyl)amino}butyric acid methyl ester in 3 ml dioxan, and stir for 16 h at RT. After adding 0.7 ml 1 N hydrochloric acid, extract with ethyl acetate. Re-extract the aqueous phase twice more with ethyl acetate. Combine the organic phases, dry over sodium sulphate, and filter. Concentrate the filtrate by vacuum evaporation. Take up the oily residue in acetonitrile and purify by preparative RP-HPLC (gradient: water/acetonitrile). 57 mg (80% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:5][CH:4]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>N1C=CC=CC=1>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:12][C:10]2[S:11][C:7]3[C:6]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(CN2CCOCC2)c2sc(N)nc12
Solvent: c1ccncc1
Product: COc1ccc(CN2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-ylmethyl-benzothiazol-2-ylamine and 4-fluoro-benzoyl chloride in pyridine the title compound was obtained as a yellow solid (44% yield), MS: m/e=402.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([NH:10][CH3:11])[CH:3]=1>ClCCl.C1COCC1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH3:11])[C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: CNc1cc(Cl)ncc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNc1cc(Cl)ncc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (4.2 g, 24.7 mmol) and manganese(IV) oxide (active, 25.8 g, 296.6 mmol) in dichloromethane (50 mL) and THF (50 mL) was stirred at RT overnight. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated to afford the title compound (3.7 g, crude) as a light yellow solid, which was directly used in the next step without further purification. MS (ES+) C7H7ClN2O requires: 170, 172. found: 171, 173 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([NH:38][C:16]([C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:18])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc(C(=O)NCc3ccccc3)ccc21
Yield: 83.7 %

Procedure:
To a suspension of 9-Ethyl-9H-carbazole-3-carboxylic acid (75 mg, 0.313 mmol) in CH2Cl2 (1 ml) at room temperature was added CDI (56 mg, 0.344 mmol) ) in CH2Cl2 (1 ml), and after stirring for 30 minutes benzylamine (38 μl, 0. 344 mmol) was added. When the reaction was complete the reaction mixture was directly loaded onto a silica column and eluted with CH2Cl2 to afforded the desired product as a white foam (86 mg, 84% yield). MS m/z @ 329 (m+1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[CH:26]1[C:35]2[C:30](=[C:31]([NH:36]N)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1>>[CH:26]1[C:35]2[C:30](=[C:31]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[C:16]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1
Reactant: NNc1cccc2cnccc12
Reactant: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4cnccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzenesulfonamide (A-31) and isoquinolin-5-yl-hydrazine according to the method described for example 91. MS: M=459.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[C:10]1[CH3:22])=[O:4].[CH:26]1([C:29]2[CH:30]=[C:31]([C@@H:35]([NH2:37])[CH3:36])[CH:32]=[CH:33][CH:34]=2)[CH2:28][CH2:27]1>>[CH:26]1([C:29]2[CH:30]=[C:31]([C@@H:35]([NH:37][C:18]([C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:9]([CH2:8][C:7]3[CH:6]=[C:5]([CH:25]=[CH:24][CH:23]=3)[C:3]([O:2][CH3:1])=[O:4])[C:10]([CH3:22])=[C:11]4[CH3:21])=[O:20])[CH3:36])[CH:32]=[CH:33][CH:34]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: C[C@H](N)c1cccc(C2CC2)c1
Product: COC(=O)c1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C5CC5)c4)ccc32)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 5, Example 35, using 1-(3-(methoxycarbonyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and (S)-1-(3-cyclopropylphenyl)ethanamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[N:17]=O>[Pd].CO>[NH2:17][C:3]1[C:4](=[O:16])[N:5]([CH3:15])[C:6](=[O:14])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]=1[NH2:1]
Reactant: Cn1c(=O)c(N=O)c(N)n(-c2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)c(N)c(N)n(-c2ccccc2)c1=O
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
The obtained 6-amino-3-methyl-5-nitroso-1-phenyluracil (0.25 g) and 5% Pd/C (20 mg) were added to 50 ml of methanol and purging with hydrogen gas was performed, followed by stirring at 70° C. for 2.5 hours. The reaction mixture was filtered while hot to give a filtrate. The solvent methanol was distilled off from the filtrate to yield 5,6-diamino-3-methyl-1-phenyluracil (yield: 0.2 g, or 86% based on 6-amino-3-methyl-5-nitroso-1-phenyluracil).
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8]([OH:16])[C:9]3[S:15][CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:24][C:25]([F:31])([F:30])[S:26](O)(=[O:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:31])([F:30])[S:26]([O:16][C:8]1[C:9]2[S:15][CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:7]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Oc1nc(C2CCCC2)nc2c1SCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1nc(C2CCCC2)nc2c1SCCC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a suspension of 2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol (2.9 g, 12.3 mmol) in methylene chloride (100 mL) at 0° C. was added N,N-dimethylaminopyridine (0.020 g, cat.), triethylamine (3.5 mL, 24.6 mmol) and trifluoromethanesulfonic acid (2.3 mL, 13.5 mmol). The suspension was warmed to rt and stirred for 3 h. The mixture was cooled to 0° C. and the reaction was quenched with a saturated solution of NaHCO3. The organic layer was washed a saturated solution of NaHCO3 and brine. The organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (3.40 g, 75%) as, a yellow solid. MW=368.40. 1H NMR (CDCl3, 500 MHz) δ 3.28-3.20 (m, 1H), 3.10-3.05 (m, 1H), 2.98 (t, J=6.5 Hz, 2H), 2.31-2.24 (m, 2H), 2.09-1.99 (m, 2H), 1.89-1.76 (m, 4H), 1.70-1.62 (m, 2H); APCI MS m/z 369 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(Cl)[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1>[Ni].C(O)(C)(C)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][N:10]([CH:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Ni]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Fc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 80 °C
Yield: 87.5 %

Procedure:
To a stirred suspension of Raney Nickel (2.0 g, wet slurry) in tertiary butanol (10 mL) and toluene (50 mL) was added a solution of 3-(4-fluorophenyl)-3-chloro-1-(diphenylrnethyl)azetidine (16) (1.9 g) in toluene (20 mL). The mixture was heated to 80° C. for 6 hours, cooled and filtered through kieselguhr. The filtrate was concentrated in vacuo and partitioned between diethyl ether (3×30 mL) and aqueous potassium carbonate solution (50 mL). The combined organic extracts were washed (water, brine), dried (Na2SO4), and concentrated in vacuo. Recrystallisation from diisopropyl ether gave 3-(4-fluorophenyl)-1-(diphenylmiethyl)azetidine (17) (1.5 g), m.p. 65-66° C. (diisopropyl ether). Found: C, 83.25; H1 6.35; N, 4.41. C22H20FN requires C, 8325; H, 6.35; N, 4.41%.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([OH:8])[CH2:5][CH2:6][CH3:7].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])[C:11]=1[C:12]#[N:13]
Reactant: CCCC(O)CCC
Reactant: N#Cc1c(N)cccc1F
Product: CCCC(CCC)Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from heptan-4-ol and 2-amino-6-fluorobenzonitrile as a white solid (24%). 1H NMR (400 MHz, CDCl3) δ 0.92 (t, J=7.2 Hz, 6H), 1.55-1.31 (m, 8H), 3.88 (s, br, 1H), 4.33-4.27 (m, 1H), 6.26 (d, J=8.0 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:12]=1[CH2:21][O:22][CH3:23]>CCO>[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH2:21][O:22][CH3:23]
Reactant: COCc1cc(C(=O)OC)ccc1-c1cccc(F)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1Cl

Procedure:
A 5N aqueous solution of NaOH (2.3 mL, 11.5 mmol) was added into a solution of methyl 2′-chloro-3′-fluoro-2-(methoxymethyl)biphenyl-4-carboxylate (2.38 g, 7.7 mmol) in EtOH (25 mL) and heated at reflux for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was taken up with water (30 mL) and a 5N aqueous solution of HCl (4 mL), and then extracted with MTBE (100 mL, then 50 mL). The organic layers were washed with brine, combined, dried (MgSO4) and treated with activated charcoal. After filtration through a Celite pad, the solution was concentrated under vacuum. After purification by crystallization from a mixture of MTBE and heptane, the title compound was obtained as a white powder (2.01 g, 88%). HPLC (Method A) Rt 4.1 min (Purity: 99.5%). LC/MS (Method B): 293.0 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.13 (s, 1H), 8.10 (d, J=1.7 Hz, 1H), 7.94 (dd, J=8.0, 1.7 Hz, 1H), 7.54-7.44 (m, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.23-7.18 (m, 1H), 4.23 (d, J=12.7 Hz, 1H), 4.15 (d, J=12.7 Hz, 1H), 3.17 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[C:26]([F:34])[C:25]=1[F:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:31](=[O:32])[CH2:30][C:27]2[CH:28]=[CH:29][C:24]([Br:23])=[C:25]([F:35])[C:26]=2[F:34])=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Reactant: O=C(O)Cc1ccc(Br)c(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cc1ccc(Br)c(F)c1F)Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 29.7 %

Procedure:
To a solution of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (20 mg, 0.064 mmol), 2-(4-bromo-2,3-difluorophenyl)acetic acid (48.4 mg, 0.077 mmol) and DIEA (0.034 mL, 0.193 mmol) in DCM (3 mL) stirred under a N2 atmosphere at 20° C. was added HATU (29.3 mg, 0.077 mmol) in one charge. The reaction mixture was stirred at 20° C. for 2 h. Then the solution was distributed between DCM and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=5:1, Rf 0.3) to yield a light yellow solid of N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,3-difluorophenyl)acetamide (12 mg, 0.019 mmol, 29.9% yield): 1H NMR (400 MHz, CDCl3) δ 7.69-7.59 (m, 2H), 7.36-7.24 (m, 6H), 7.05 (t, J=7.3 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 4.64 (s, 2H), 4.20 (t, J=4.4 Hz, 2H), 3.86 (t, J=4.8 Hz, 2H), 3.71 (s, 2H); ES-LCMS m/z 546.0 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=1)#[N:2].[H][H]>C(O)(=O)C.[Pd]>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C#N)n3)c2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(CN)n3)c2)cc1
Yield: 65.1 %

Procedure:
6-Cyano-4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine (1 mmol) in 33 ml of glacial acetic acid was reduced with hydrogen in the presence of 0.1 g of 10% palladium catalyst on carbon in a Parr apparatus at 40-50 psi and 40°-45° C. for three days. The catalyst was removed by filtration under nitrogen, and the product was purified using a silica gel column by elution with 2.5% ammonium hydroxide/5% methanol/92.5% methylene chloride to yield 0.24 g (65%) of product as a hemi-hydrate. 1H NMR (CDCl3): 1.87 (singlet (s), exchanges with D2O); 3.90 (s, 3H, MeO--); 4.12 (s, 2H, terpyridyl-CH2 --N), 7.08 (doublet (d), 2H, phenyl); 7.35 (multiplet (m), 2H); 7.90 (m and d, 4H); 8.55 (d, 1H); and 8.70 ppm (m, 4H). Calculated: C, 73.19%; H 5.61%; N, 14.84%. Found: C, 72.95%; H, 5.43%; N, 14.61%.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Br[CH2:34][CH2:35][OH:36]>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:34][CH2:35][OH:36])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: OCCBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1CCO

Procedure:
(5Z)-5-[(1-{[2,4-Bis(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-(2-hydroxyethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 238) and 2-bromoethanol following General Procedure H.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[C:11](=O)[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2].[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl>C(O)C>[ClH:27].[CH2:1]([O:3][C:4]([C:6]1[C:10]2/[C:11](=[N:26]/[NH:25][C:22]([NH2:24])=[NH:23])/[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: N=C(N)NN
Reactant: CCOC(=O)c1coc2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1coc2c1/C(=N/NC(=N)N)CC(c1ccccc1)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a mixture of 3-ethoxycarbonyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.28 g) and aminoguanidine hydrochloride (111 mg) were ethanol (20 ml) and 6N hydrochloric acid (0.086 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-3-ethoxycarbonyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 55) (0.25 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16](=[CH:17][C:18](=[O:19])[CH:20]=[CH:21]2)[CH:15]=[CH:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 56 %

Procedure:
1,4,6-cholestatrien-3 one was prepared in 56% yield from cholesterol, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and dioxane by the procedure of A. B. Turner J. Chem. Soc. C, 2568 (1968).
Reaction SMILES: [OH:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CS(C)=O>[O:1]=[C:2]([CH3:18])[CH2:3][N:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11][C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: CC(O)CN1c2ccccc2Sc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CN1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound (1) (2.52 g, 9.79 mmol) obtained above and triethylamine (9.5 ml, 68 mmol) in dimethyl sulfoxide (25 ml) was added a solution of sulfur trioxide-pyridine complex (4.67 g, 29.3 mmol) in dimethyl sulfoxide (25 ml), and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and thus obtained brown solid was purified by column chromatography on silica gel to give pale green needle-like crystals. Yield 1.93 g (77%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:9]=[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19]([Br:23])[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:12]([CH3:24])[C:11]2=[O:25])[C:7]([CH3:26])=[N:6]1.CO.[BH4-].[Na+]>C1COCC1>[Br:23][C:19]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:12]([CH3:24])[C:11](=[O:25])[N:10]([C:8]4[C:7]([CH3:26])=[N:6][N:5]([CH2:4][CH2:3][OH:2])[CH:9]=4)[C:22]=3[C:21]=2[CH:20]=1
Reactant: COC(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(CCO)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Temperature: 0 °C

Procedure:
A mixture of [4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (Stage 101.1.1a, 60 mg, 0.139 mmol) and MeOH (0.021 ml, 0.519 mmol) in THF (1.5 ml) was cooled to 0° C. Then NaBH4 (14 mg, 0.370 mmol) was added and the RM was heated to 50° C. for 30 min. After that, the RM was quenched with saturated aqueous NaHCO3 (20 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a lightly yellow solid. (HPLC: tR 2.23 min (Method A); M+H=402, 404 Br-Pattern MS-ES)