Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].CC1C(O)=C(C)C2CC[C@](CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)(C)OC=2C=1C.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/C1C(C)(C)CCCC=1C>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Agent: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The food additive is prepared by combining a sterol and/or stanol ester of a fatty acid made by the process described herein and an edible solubilizing agent, an effective amount of a suitable antioxidant and an effective amount of a suitable dispersant. The solubilizing agent can be vegetable oil such as, for example, sunflower oil, palm kernel oil, coconut oil, rape seed oil, tallow, corn oil, canola oil, linseed oil, palm oil, olive oil, sesame oil, safflower oil, and the like, monoglycerides, diglycerides, triglycercides, tocopherols, and the like, and mixtures thereof. The antioxidant can be ascorbic acid (Vitamin C), tocopherols such as α-tocopherol (vitamin E), β-carotene, an extract of the bark of the maritime pine, Pinus maritima and combinations thereof. The extract of the bark of the maritime pine, also known as PYCNOGENOL™, contains procyanidines consisting of catechin and epicatechin units linked by C—C bonds to form dimers, trimers and other oligomers up to a chain length of 6-7 molecules and phenolic acids and its glucose derivatives. PYCNOGENOL™ is produced according to U.S. Pat. No. 4,698,360, which is incorporated herein for reference. The extract used according to the invention may be prepared essentially by extracting maritime pine bark in comminuted form with boiling water, saturating the filtered extract with sodium chloride or, alternatively, adding ammonium sulfate to 20% w/v, separating the precipitate formed, repeatedly extracting the supernatant with 1/10 volume of ethyl acetate, drying the collected ethyl acetate extracts, concentrating the dried extract, pouring it into 3 volumes of chloroform with stirring and collecting the precipitate which may be purified by repeating the dissolution in ethyl acetate and precipitation with chloroform. Mixtures of the above antioxidants can also be used.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]1OC2(CCCC2)[O:7][C@@H:6]([CH2:14][C:15]([OH:17])=[O:16])[CH2:5]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH:26]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:27]([C:37](=O)[CH:38]([CH3:40])[CH3:39])[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])=[CH:21][CH:20]=1.C(OCC)C.[Cl-].[NH4+]>CS(C)=O.O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:1]([CH2:2][CH2:3][C@H:4]3[CH2:5][C@H:6]([OH:7])[CH2:14][C:15](=[O:16])[O:17]3)[C:37]([CH:38]([CH3:40])[CH3:39])=[C:27]([C:28]([NH:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:29])[C:26]=2[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:23][CH:24]=1
Reactant: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCC2)O1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@H]1C[C@H](O)CC(=O)O1
Temperature: 105 °C
Reaction time: 3 h
Yield: 24.7 %

Procedure:
A solution of 0.295 g (1.21 mmol) of (±)-cis-9-(2-aminoethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid and 0.504 g (1.20 mmol) of (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers in 5 mL of dimethyl sulfoxide is heated at 105° C. for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with water (2×50 mL) and 5% sodium hydroxide solution (2×100mL--to extract the intermediate protected acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2 H-pyran-2-yl)ethyl]-1 H-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.16 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2 H-pyran-2-yl)ethyl]-1 H-pyrrole-3-carboxamide is isolated in two crops.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: Cc1cc(Sc2ccccc2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(Sc2ccccc2)cc(C)c1-c1csc(N)n1
Yield: 88.9 %

Procedure:
A reaction mixture containing 2-bromo-1-(2,6-dimethyl-4-(phenylthio)phenyl)ethanone (591.7 mg, 1.8 mmol, 1.0 equiv) and thiourea (134.3 mg, 1.8 mmol, 1.0 equiv) in EtOH (15.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(2,6-dimethyl-4-(phenylthio)phenyl)thiazol-2-amine (483.7 mg, 1.6 mmol) as yellow solids in 88% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.33-7.38 (m, 2 H), 7.29-7.33 (m, 3 H), 7.06 (brs, 2 H), 6.89 (s, 2 H), 6.38 (s, 1 H), 2.07 (s, 6 H); ESI-MS: m/z 313.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cn[nH]c4)cc23)CC1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (41 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: CN(C)[C:3](=[O:12])[C@@H:4]([CH3:11])[O:5][CH:6]([O:8][CH2:9][CH3:10])[CH3:7].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Mg]Br.FC1C=C(F)C=CC=1Br.[Mg].[Cl-].[NH4+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH2:9]([O:8][CH:6]([O:5][C@H:4]([CH3:11])[C:3]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][C:19]=1[F:21])=[O:12])[CH3:7])[CH3:10]
Reactant: CCOC(C)O[C@H](C)C(=O)N(C)C
Reactant: Fc1ccc([Mg]Br)c(F)c1
Agent: Fc1ccc(Br)c(F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(C)O[C@H](C)C(=O)c1ccc(F)cc1F
Reaction time: 8 h

Procedure:
N,N-Dimethylamine (405.7 g, 9.0 mol) was blown in a solution of (D)-methyl lactate (469 g, 4.5 mol) in methanol (234 mL) at 0-15° C. and the solution was stirred in a sealed vessel at 60-65° C. for 24 hr. The reaction mixture was concentrated under reduced pressure to give (D)-N,N-dimethyl lactamide (525 g). To the solution of a part (109 g, 0.93 mol) of the obtained (D)-N,N-dimethyl lactamide in THF (97 mL) were successively added dropwise methanesulfonic acid (0.9 g, 9.4 mmol) and ethyl vinyl ether (74 g, 1.03 mol) at 15-20° C. and the mixture was stirred for 5 hr to give a solution of (2R)-N,N-dimethyl-2-O-(1-ethoxyethyl)lactamide in THF. Subsequently, to this amide solution was dropwise added a solution of 2,4-difluorophenylmagnesium bromide, which had been synthesized from 2,4-difluorobromobenzene (180 g, 0.93 mol) and magnesium (23 g, 0.95 mol) by a conventional method, in THF (485 mL) at room temperature. The mixture was stirred overnight. The reaction solution was flown into cooled aqueous ammonium chloride solution, neutralized with aqueous citric acid solution and extracted 3 times with toluene. The organic layer was mixed and the mixture was washed successively with aqueous ammonium chloride solution and water to give a solution of (2R)-2-(1-ethoxyethoxy)-1-(2,4-difluorophenyl)-1-propanone in toluene. Subsequently, methanol (97 mL) and methanesulfonic acid (0.9 g, 9.4 mmol) were added, and the mixture was stirred at 40° C. for 2.5 hr. The reaction mixture was washed successively with 5% brine (once) and water (two times) and the organic layer was concentrated under reduced pressure to give the title compound as a pale-yellow oil (120 g, yield 69%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.ClC1C=CC=C(C(OO)=[O:20])C=1.C1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N+:3]([O-:20])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1cc2ccccc2cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccccc1
Product: [O-][n+]1cc2ccccc2cc1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 32.6 %

Procedure:
A mixture of 3-chloroisoquinoline (18.23 g), m-chloroperbenzoic acid (36.46 g) and benzene (180 ml) was stirred at ambient temperature for a period of 2.5 days. The mixture was diluted with dichloromethane and the resultant solution was washed several times with a aqueous 5% sodium bicarbonate solution and finally with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated to give a solid residue. The solid was recrystallised from ethyl acetate to give 3-chloroisoquinoline-2-oxide (6.53 g) as colourless crystals mp 147°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([O:14]CC)=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1n[nH]c2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(C(=O)O)n[nH]c2c1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To ethyl 6-methoxy-1H-indazole-3-carboxylate (0.415 mmol) in methanol (5 ml) was added 4N sodium hydroxide (aq) (8 mL, 32.0 mmol). After two hours stirring, reaction was still not finished and 6 ml of 4N NaOH was added. Upon completion of the reaction, the methanol was removed by evaporation and the water layer was washed with ethyl acetate. Subsequently the water layer was acidified and extracted with ethyl acetate twice. The latter organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give 6-methoxy-1H-indazole-3-carboxylic acid (64 mg) as a brown solid.
Reaction SMILES: C([O:9][CH:10]1[CH2:17][CH:16]2[CH:12]([CH2:13][C:14](=[O:18])[O:15]2)[CH:11]1[CH:19]1[O:23][CH2:22][CH2:21][O:20]1)(=O)C1C=CC=CC=1.C[O-].[Na+].CCCCCC.C(OCC)(=O)C>CO.C(Cl)Cl>[CH:19]1([CH:11]2[CH:10]([OH:9])[CH2:17][CH:16]3[CH:12]2[CH2:13][C:14](=[O:18])[O:15]3)[O:23][CH2:22][CH2:21][O:20]1
Reactant: O=C1CC2C(CC(OC(=O)c3ccccc3)C2C2OCCO2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1CC2C(CC(O)C2C2OCCO2)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a well stirred solution of crude 1b (63.85 g, 201 mmol, 1 eq) in methanol (786 mL) at 0° C. is added a suspension of sodium methoxide (13.27 g, 246 mmol, 1.2 eq) in MeOH (98.3 mL). The reaction is stirred at 0° C. for 1 hour and then is warmed to 25° C. for 1 hour. The reaction is neutralized with acidic ion exchange resin which has been washed thoroughly with MeOH (5×100 mL). The filtrate is concentrated in vacuo to give a syrup which is subjected to flash chromatography on silica gel eluting with 4:1 hexane:ethyl acetate and 2% MeOH in CH2Cl2 to give 1c as a yellow syrup.
Reaction SMILES: NC1SC(C2C(F)=CC=CC=2F)=NC=1C(NC1C=NN(C)C=1N1CCC(C(F)F)C(N)CC1)=O.[F:35][C:36]([F:59])([F:58])[C:37]([NH:39][C@H:40]1[CH:46]([CH:47]=[O:48])[CH2:45][CH2:44][N:43]([C:49]2[N:50]([CH3:57])[N:51]=[CH:52][C:53]=2[N+:54]([O-:56])=[O:55])[CH2:42][CH2:41]1)=[O:38].[BH4-].[Na+]>CO>[F:58][C:36]([F:35])([F:59])[C:37]([NH:39][C@H:40]1[CH:46]([CH2:47][OH:48])[CH2:45][CH2:44][N:43]([C:49]2[N:50]([CH3:57])[N:51]=[CH:52][C:53]=2[N+:54]([O-:56])=[O:55])[CH2:42][CH2:41]1)=[O:38]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(C=O)[C@H](NC(=O)C(F)(F)F)CC1
Agent: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)C(C(F)F)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(CO)[C@H](NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 62 %

Procedure:
In the preparation of 511, 2,2,2-trifluoro-N-[(4R)-5-formyl-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]acetamide (192 mg, 0.53 mmol) was dissolved in methanol (5 mL) and cooled in an ice bath. Sodium borohydride (41 mg, 1.06 mmol) was added, allowed to warm to room temperature, and stirred for 40 min. The reaction was quenched with sat. NaHCO3 and extracted with EA 3×. The combined organic layers were concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to give 2,2,2-trifluoro-N-[(4R)-5-(hydroxymethyl)-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]acetamide (120 mg, 62%).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH2:21][CH2:22][CH3:23]>>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:24][C:20]([CH2:21][CH2:22][CH3:23])=[N:25][C:11]=3[C:10]=2[CH:13]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Reactant: CCCC(=N)N
Agent: Cl
Product: CCCc1ncc2c(n1)-c1cc(F)ccc1NC(=O)C2
Yield: 50 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and butyramidine hydrochloride. Yield: 50%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH:26]=[CH2:27]>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH2:26][CH2:27][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5]2[C@H:16]3[NH:17][C@@H:12]([CH2:11][C:6]1=2)[CH2:13][CH2:14][CH2:15]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C=Cc1cc(C)ccc1C
Product: Cc1ccc(C)c(CCn2c3c(c4cc(C)ccc42)[C@@H]2CCC[C@H](C3)N2)c1

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.486 mmol; Example 118A) and 1,4-dimethyl-2-vinylbenzene (129 mg, 0.972 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound as the first-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.07-1.35 (m, 3H), 1.60-1.96 (m, 4H), 1.99 (s, 3H), 2.15 (s, 3H), 2.41 (s, 3H), 2.82 (dd, J=17, 7 Hz, 1H), 2.94-3.16 (m, 2H), 3.38-3.45 (m, 1H), 4.19 (ddd, J=15, 9, 5 Hz, 1H), 4.30-4.41 (m, 2H), 6.69 (s, 1H), 6.84-6.99 (m, 3H), 7.14 (s, 1H), 7.27 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 359 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH:23]2[O:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:2]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH:23]2[O:28][CH2:27][CH2:26][N:25]([CH3:31])[CH2:24]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: Cc1ccc(OCC2CNCCO2)c(NC(=O)Nc2cnc(C#N)cn2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(OCC2CN(C)CCO2)c(NC(=O)Nc2cnc(C#N)cn2)c1
Reaction time: 12 h
Yield: 28.4 %

Procedure:
A solution of 1-(5-cyano-pyrazin-2-yl)-3-[5-methyl-2-(morpholin-2-ylmethoxy)-phenyl]-urea hydrochloride salt (0.0104 g, 0.129 mmol) in MeOH (1 mL) was cooled to 0° C. and treated with an aqueous solution of formaldehyde (0.12 mmol) followed by sodium triacetoxy borohydride (0.06 g, 0.292 mmol). The reaction was stirred for 12 h, then concentrated in vacuo. The residue was chromatographed on silica (2% MeOH in CH2Cl2) to give the product as a white solid (0.014 g). 1H-NMR (400 MHz, d6-DMSO) δ 10.90 (s, 1, H), 10 (br s, 1, H), 8.9 (s, 1, H), 8.8 (s, 1, H), 8 (s, 1, H), 6.9 (m, 1, H), 6.8 μm, 1, H), 3.9 (m, 4, H), 3.6 (t, 1, H), 2.9 (d, 1, H), 2.7 (d, 1, H), 2.2 (s, 3, H), 2.1 (s, 3, H), 2 (t, 1, H), 1.8 (t, 1, H). LRMS (esi, positive) m/e 383.40 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[CH:23]=[C:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][CH2:27][C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]1=2>>[CH:35]1[C:26]2[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:24](=[CH:23][C:3]3[CH:4]=[C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:6]=[CH:7][C:2]=3[CH3:1])[C:25]=2[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccc(NS(C)(=O)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Product: Cc1ccc(NS(C)(=O)=O)cc1C=C1c2ccccc2CCc2ccccc21
Yield: 60.7 %

Procedure:
Following the procedures essentially as described in Example 219, below, and using N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide (120 mg, 0.386 mmol) and 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.351 mmol) affords 83 mg (61%) of the title compound as a yellow solid. MS (ES) 407 (M+NH4), 388 (M−H); HPLC shows 91% purity.
Reaction SMILES: [Cl:1][C:2]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)=[CH:14][C:6]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl>CN(C=O)C>[Cl:1][C:2]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:19]=[N:18][N:17]([CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[CH:16]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4cn[nH]c4)cc32)c1Cl
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(-c2cnc3c(c2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cn1
Temperature: 25 °C
Reaction time: 312 h
Yield: 9 %

Procedure:
Anhydrous DMF (2 mL) was added to a mixture of 1-(2-chloro-3,6-difluorobenzyl)-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (57 mg, 0.000158 mol), cesium carbonate (0.110 g) and 2-dimethylaminoethyl chloride HCl (0.025 g). The reaction mixture was stirred at room temperature under nitrogen for 13 days and then concentrated and dissolved in methylene chloride. The organic phase was washed with water, dried with magnesium sulfate, filtered, and concentrated. The residue was purified on normal phase silica gel chromatography to give the title compound as an off-white solid (9% yield). LCMS: m/z=433.13 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.30 (6H, s), 2.79 (2H, t, J=6.8 Hz), 3.29 (2H, t, J=4.7 Hz), 3.51 (2H, m), 4.24 (2H, t, J=6.8 Hz), 4.50 (2H, s), 4.77 (1H, bs), 6.97 (1H, s), 7.02 (1H, m), 7.12 (1H, m), 7.60 (1H, s), 7.63 (1H, d, J=1.5 Hz), 7.66 (1H, s).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH2:12]O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>N1C=CC=CC=1>[Cl:23][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccccc2)cs1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClCc1cc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Phenyl thiophene-2-methanol (0.21 g), toluene (2.0 mL), and a catalytic amount of pyridine were added, and thionyl chloride (0.16 mL) was added dropwise thereto under ice-cooling. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried at 60° C. under reduced pressure to obtain 2-(chloromethyl)-4-phenylthiophene (0.22 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:53])([CH3:52])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:51])([C@@:18]4([CH3:50])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][N:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:42][CH2:41]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:53])([CH3:52])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:51])([C@@:18]4([CH3:50])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][N:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:44][CH2:45]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 52.7 %

Procedure:
To a solution of methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.056 g, 0.074 mmol) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.372 mL, 0.372 mmol). The mixture was heated to 60° C. for 6.5 h then was cooled to rt. The mixture was diluted with methanol and 1,4-dioxane, was filtered through a plug of glass wool and was purified by prep HPLC. The fractions containing the expected product were combined and were concentrated under reduced pressure to give 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (30.1 mg, 0.039 mmol, 52.0% yield) as a white solid. LCMS: m/e 738.6 (M+H)+, 1.66 min (method 2). 1H NMR (400 MHz, Acetic acid d4) 67.92 (t, J=7.9 Hz, 1H), 7.04 (dd, J=8.0, 1.5 Hz, 1H), 7.01-6.96 (m, 1H), 5.38 (d, J=5.0 Hz, 1H), 4.81 (s, 1H), 4.70 (s, 1H), 3.59-3.25 (m, 8H), 3.15 (br. s., 4H), 2.90 (s, 3H), 2.94-2.81 (m, 1H), 1.72 (s, 3H), 1.21 (s, 3H), 1.09 (s, 3H), 1.04 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 2.23-0.83 (m, 22H).