Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[S:37][C:36]([C:38](Cl)=[O:39])=[CH:35][CH:34]=1.[N:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH2:75][CH2:74][C:50]3([CH2:55][CH2:54][N:53]([C:56]([C:58]4[N:59]=[C:60]5[CH2:65][N:64](C(OC(C)(C)C)=O)[CH2:63][CH2:62][N:61]5[CH:73]=4)=[O:57])[CH2:52][CH2:51]3)[CH2:49][CH2:48]2)=[CH:43][CH:42]=1>C(Cl)Cl>[Cl:32][C:33]1[S:37][C:36]([C:38]([N:64]2[CH2:63][CH2:62][N:61]3[CH:73]=[C:58]([C:56]([N:53]4[CH2:52][CH2:51][C:50]5([CH2:74][CH2:75][N:47]([C:44]6[CH:43]=[CH:42][N:41]=[CH:46][CH:45]=6)[CH2:48][CH2:49]5)[CH2:55][CH2:54]4)=[O:57])[N:59]=[C:60]3[CH2:65]2)=[O:39])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCn2cc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)nc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cn2c(n1)CN(C(=O)c1ccc(Cl)s1)CC2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Reaction time: 0.5 h
Yield: 11 %

Procedure:
EDCl (1.29 mmol, 1.5 equiv.), HOBt (1.29 mmol, 1.5 equiv.) and DIPEA (3.44 mmol, 4 equiv.) were added at 0° C. to a solution of 5-chlorothiophene-2-carbonyl chloride (0.86 mmol, 1.0 equiv.) in DCM (20 ml), and the mixture was stirred for 30 min. A solution of tert-butyl 2-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (0.86 mmol, 1.0 equiv.) in DCM (5 ml) was then added, the ice bath was removed, and stirring was carried out for 16 h at 25° C. The reaction mixture was diluted with dichloromethane (100 ml) and washed with sat. sodium carbonate solution (65 ml), sat. ammonium chloride solution (65 ml), water (50 ml) and sat. sodium chloride solution (50 ml), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (8% methanol in DCM) and the desired product was thus obtained in the form of a white solid. Yield: 11%. MS, Rt=2.7 min; m/z=525.2 [MH]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH2:16]([C@@H:19]1[CH2:23][C@@H:22]([CH2:24]OS(C)(=O)=O)[N:21]([CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:20]1=[O:39])[CH:17]=[CH2:18].[OH-].[K+].Cl>O>[CH2:16]([C@@H:19]1[CH2:23][C@@H:22]([CH2:24][O:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[N:21]([CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:20]1=[O:39])[CH:17]=[CH2:18]
Reactant: N#Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: C=CC[C@@H]1C[C@@H](COS(C)(=O)=O)N(CCCc2ccccc2)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CC[C@@H]1C[C@@H](CO[C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)N(CCCc2ccccc2)C1=O

Procedure:
0.73 g of trans-4-(4-cyanophenyl)cyclohexanol, 2.8 g of (3R,5S)-3-allyl-5-[(methanesulphonyl)oxymethyl]-1-(3-phenylpropyl)-2-pyrrolidinone, 2.5 ml of 60% aqueous potassium hydroxide solution and 0.3 g of polyethyleneglycol-750 monomethylether (bound to polystyrene-1% divinylbenzene) are stirred for 24 hours at 45° C. Ice and water are added to the mixture, it is acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase is dried with sodium sulphate, concentrated by evaporation and the residue is chromatographed over a silica gel column with petroleum ether/ethyl acetate (2:1). 0.4 g (24% of theory) of product are obtained. Rf value: 0.61 (silica gel; petroleum ether/ethyl acetate 12:1) Calculated: C 78.91 H 7.95 N 6.14 Found: 78.88 8.13 6.10
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:3]=1.Cl[CH2:18][CH2:19][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH3:21]>>[CH3:22][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:21])[CH2:19][CH2:18][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)=[N:5]1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)n[nH]1
Reactant: CC(C)(CCCl)NC(=O)OC(C)(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)nn1CCC(C)(C)NC(=O)OC(C)(C)C

Procedure:
The target compound is obtained analogously to the method described for intermediate product 1c) from 4.90 g (21.6 mmol) 5-methyl-3-(4-trifluoromethyl-phenyl)-1H-[1,2,4]triazol and 7.17 g (32.4 mmol) tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate. White solid. Yield: 5.06 g (57%); mass spectroscopy [M+H]+=413.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]2.S(=O)(=O)(O)O>COCCOCCOC>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[C:14](=[CH:2][C:1]([OH:5])=[O:4])[CH2:13][CH2:12]2
Reactant: O=CC(=O)O
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: COCCOCCOC
Product: COc1ccc2c(c1)CCC(=CC(=O)O)C2=O
Temperature: 85 °C
Yield: 85.5 %

Procedure:
Glyoxalic acid (30 mL, 303 mmol) and water (14 mL) were added to a stirred solution of 6-methoxy tetralone (25 g, 141 mmol) in diglyme (50 mL) followed by sulphuric acid (6.5 mL, 35 mmol). The reaction mixture was heated to 85° C. overnight. The reaction mixture was cooled to 0° C., and resulting solids were filtered off and washed with water (3×25 mL), dried under reduced pressure to afford title compound (28 g, 85%) as solid. 1H NMR (300 MHz, DMSO-d6): δ 12.9 (bs, 1H), 7.9 (d, J=8.4 Hz, 1H), 7.0 (m, 2H), 6.6 (s, 1H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (m, 2H). ESI-MS m/z: 233 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:25]#[N:26])[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[NH4+].CO>[Fe].O>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][CH3:24])[N:13]=[CH:12][C:11]([C:25]#[N:26])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Yield: 8428.4 %

Procedure:
An amount of 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-6-nitro-quinoline-3-carbonitrile (9.9 g, 0.27 mmol) was combined with ammonium chloride (11.4 g, 0.21 mol), iron powder (8.9 g, 0.16 mol), methanol (200 mL), and water (50 mL), and heated at reflux for 2 hours. An additional amount of iron (1.0 g, 0.018 mol) and ammonium chloride (1.0 g, 0.019 mol) were added and the mixture was refluxed for an additional 3.5 hours. The reaction mixture was filtered hot and the residue was washed with boiling methanol to extract the product. The filtrate was evaporated to a slurry and stirred with saturated sodium bicarbonate solution and ethyl acetate. The layers were separated, and the organic layer was dried over magnesium sulfate and evaporated to dryness to give a green powder (7.8 g, 85%), which was used without further purification.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[F:6][C:7]([F:15])([F:14])[C:8]#[C:9][C:10]([F:13])([F:12])[F:11]>>[F:6][C:7]([F:15])([F:14])[C:8]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]2[CH2:5][C:1]=1[CH2:2][CH2:3]2
Reactant: FC(F)(F)C#CC(F)(F)F
Reactant: C1=CCC=C1
Product: FC(F)(F)C1=C2CCC(=C1C(F)(F)F)C2

Procedure:
Reaction of cyclopentadiene with hexafluorobut-2-yne at 100° C. for 24 hours gives 2,3-bis(trifluoromethyl)bicyclo [2.2.1] heptadiene which, upon hydrogenation over platinum, gives 2,3-bis(trifluoromethyl)bicyclo [2.2.1] heptane.
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:8][CH:9]([O:25][CH2:26][CH3:27])[C:10]1[C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:24])[C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH3:7].CN(C)CCN(C)C.[CH:36](N1CCCCC1)=[O:37].Cl>C(OCC)C.C(OCC)(=O)C>[CH2:6]([O:8][CH:9]([O:25][CH2:26][CH3:27])[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:23]=1[S:22][C:21]1[C:20]([CH:36]=[O:37])=[CH:19][CH:18]=[CH:17][C:16]=1[N:15]2[CH3:24])[CH3:7]
Reactant: O=CN1CCCCC1
Reactant: CCOC(OCC)c1cccc2c1Sc1ccccc1N2C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(OCC)c1cccc2c1Sc1c(C=O)cccc1N2C
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 19.1 %

Procedure:
7.4 ml of tert-butyllithium solution (1.4M in pentane) were slowly added dropwise under argon and at -78° to a solution of 2.5 g (7.93 mmol) of 4-diethoxymethyl-10-methyl-phenothiazine and 2.4 ml of N,N,N',N'-tetramethylethylenediamine in 25 ml of diethyl ether. The reaction mixture was brought slowly to room temperature, stirred for 3.5 hours and then treated with 1.32 ml (11.9 mmol) of N-formylpiperidine. The reaction mixture was stirred at 0° for 1 hour and then poured into 30 g of ice, 30 ml of 0.1N aqueous hydrochloric acid solution and 70 ml of ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over magnesium sulphate and evaporated. The residue was chromatographed on 200 g of silica gel with ethyl acetate/hexane (1:4), whereupon 310 mg (12.4%) of starting product and, after crystallization from ethyl acetate/hexane, 520 mg (19%) of 6-diethoxymethyl-10-methylphenothiazine-4-carbaldehyde were obtained as a yellow solid of m.p. 154°-154.5°.
Reaction SMILES: C([O:8][CH:9]([CH2:30][O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35][Br:36])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C1C=CC=CC=1>[Pd].C(O)(=O)C>[Br:36][CH2:35][CH2:34][NH:33][C:32]([O:31][CH2:30][CH:9]([OH:8])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:37]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COC(=O)NCCBr)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOCC(O)COC(=O)NCCBr
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A 40 ml portion of 90% aqueous acetic acid solution was added to 949 mg (1.623 mmole) of 2-benzyl-3-O-(2'-bromoethyl)carbamoyl-1-octadecylglycerol (as synthesized in Example 7) and 250 mg of 10% Pd/C, and hydrogenolysis was carried out at room temperature for 2 hours. After the catalyst was filtered out, the filtrate was concentrated under reduced pressure, and a mixture of n-hexane-ethyl acetate (2:1) was added to the residue. The precipitate was collected by filtration to give 785 mg (97.8 g) of the alcohol derivative (colorless powder).
Reaction SMILES: [N+]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[Cl:20]C1C=CC(C(Cl)=O)=CC=1>>[Cl:20][C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Product: O=C1CCCCCN1C(=O)c1ccc(Cl)cc1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII) using 4-chlorobenzoylchloride (Aldrich) in place of 4-nitrobenzoyl chloride.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([CH3:21])[CH:13]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].O.O.[Sn](Cl)Cl>C(O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH:8]2[CH2:7][CH2:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]2)=[CH:13][C:14]=1[CH3:21]
Reactant: CCCCN1CCC(Oc2ccc([N+](=O)[O-])c(C)c2)CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCCCN1CCC(Oc2ccc(N)c(C)c2)CC1

Procedure:
In a manner similar to Preparation 44 react 1-butyl-4-(3-methyl-4-nitrophenoxy)piperidine with tin(II) chloride dihydrate in ethanol to obtain the title compound.
Reaction SMILES: [C:1]1(=[O:10])[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[CH:4]=[CH:3][NH:2]1.[H-].[Na+].[CH3:13]I>CN(C=O)C>[CH3:13][N:2]1[CH:3]=[CH:4][C:5]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:1]1=[O:10]
Reactant: O=c1[nH]ccc2c1CCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(c1=O)CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
The title compound of step 5 (260 mg, 1.93 mmol) was dissolved in DMF (5 mL) and cooled to 0° C. NaH (94 mg, 2.31 mmol) was added and the mixture was stirred for 30 min. Methyl iodide (146 μL, 2.31 mmol) was added and the mixture stirred at rt for 2 h. The volatile components were removed under vacuum and silica gel chromatography (PE/EtOAc=1:1) gave the title compound (192.6 mg, 67%) as a brown oil. 1H NMR (CD3Cl, 300 MHz): δ 7.13 (d, J=6.6 Hz, 1H), 6.13 (d, J=6.6 Hz, 1H), 3.53 (s, 3H), 2.79-2.85 (m, 4H), 2.01-2.11 (m, 2H).
Reaction SMILES: I.[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([CH3:15])[NH:6][C:7](SC)=[N:8]2.[OH-].[NH4+:17]>C(#N)C.C(O)(C(F)(F)F)=O>[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([CH3:15])[NH:6][C:7]([NH2:17])=[N:8]2
Reactant: CSC1=Nc2cccc(Cl)c2C(C)N1
Reactant: [NH4+]
Agent: I
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC1NC(N)=Nc2cccc(Cl)c21
Temperature: 130 °C
Yield: 62 %

Procedure:
5-Chloro-4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (100 mg, 0.28 mmol) was suspended in a mixture of ammonium hydroxide (1 ml, 25% in H2O) and acetonitrile (1 ml) and heated in a microwave oven to 130° C. (15 min) and subsequently to 170° C. (30 min). The title compound (35 mg, 62%) was isolated from the reaction mixture by preparative, reverse-phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) as a white solid.
Reaction SMILES: Cl.[Na].[OH:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6](Cl)[N:5]=1.[CH3:13][OH:14]>>[OH:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([O:14][CH3:13])[N:5]=1
Reactant: Cc1nc(O)nc(Cl)c1Cl
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COc1nc(O)nc(C)c1Cl
Yield: 59 %

Procedure:
Hydrogen chloride gas was passed into a suspension of 80.4 g (0.4 mole) of the sodium salt of 2-hydroxy-4-methyl-5,6-dichloropyrimidine in 600 ml of methanol until the mixture reacted strongly acid. The mixture was then stirred for a further hour and thereafter the solvent was distilled off in vacuo. The residue was triturated with 50 ml of water and filtered off. 41.3 g (59% of theory) of 2-hydroxy-4-methyl-5-chloro-6-methoxy-pyrimidine were obtained in the form of a beige powder of melting point 235° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH:17]1([NH2:21])[CH2:20][CH2:19][CH2:18]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:21][CH:17]2[CH2:20][CH2:19][CH2:18]2)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: NC1CCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NC1CCC1)c1ccc(Br)cc1OC(F)(F)F
Yield: 59.7 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and cyclobutylamine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclobutyl-2-(trifluoromethoxy)benzenesulfonamide (0.23 g, 61%) was provided after purification. MS (ESI) m/z 374. HPLC purity 100.0% at 210-370 nm, 10.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH:1]([C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:2].[Br:22]Br>C(O)(=O)C>[Br:22][C:7]1[CH:8]=[C:3]([CH:1]=[O:2])[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2C=O)CC1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2C=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
tert-Butyl 4-(3-formylpyridin-2-yl)piperazine-1-carboxylate (1.88 g) was dissolved in acetic acid (20 ml), and bromine (1.03 g) was added dropwise thereto, followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. The obtained residue was subjected to liquid separation by the addition of CHCl3 and a 1 M aqueous NaOH solution. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 4-(5-bromo-3-formylpyridin-2-yl)piperazine-1-carboxylate (2.05 g).
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H]([C@@H](CO)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.C=[C:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1>>[OH:2][CH2:1][C@H:32]1[CH2:31][CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@@H:33]1[C@H:34]1[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1C[C@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C[C@H](CO)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
7β-Hydroxymethylandrostane-3,17-dione II-aw was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-7β-hydroxymethylandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.70-3.60 (2H, m), 3.54 (1H, t), 2.50-0.90 (21H, m), 1.06 (3H, s), 0.86 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:24]([OH:30])(=[O:29])[CH2:25][CH2:26][C:27]#[CH:28]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:28]#[C:27][CH2:26][CH2:25][C:24]([OH:30])=[O:29])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Reactant: C#CCCC(=O)O
Product: COc1c(C)cnc(Cn2cc(C#CCCC(=O)O)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-Chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see Example 1) with 4-pentynoic acid according to the General Procedure A. tR=4.73 min. 1H NMR (DMSO-d) δ 12.2 (s, 1H), 8.15 (s, 1H), 7.28 (s, 1H), 6.80 (s, 2H), 5.33 (s, 2H), 3.73 (s, 3H), 3.31 (br. s, 2H), 2362 (br. t, 2H), 2.27 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:30])[CH:5]=[C:6]3[C@:27]([CH3:28])([C@@H:2]12)[C@@H:26]1[C@H:9]([C@H:10]2[C@:23]([CH3:29])([CH2:24][CH2:25]1)[C@@H:13]([C@H:14]([CH3:22])[CH2:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3>[Zn].C(O)(=O)C>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6]([CH:7]=[CH:8][C@@H:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[CH:5][C:4](=[O:30])[CH2:3]1
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The epoxide from (b) was treated with zinc dust and acetic acid as described in Example 2 (a) to yield 1α,25-dihydroxycholesta-4,6-dien-3-one, which was then converted to the trimethylsilyl ether and reduced with lithium/liquid ammonia as described in Example 2 (b). The title compound obtained in this way, (m.p. 171-173 solidifies and remelts at 178°-179°; [α]D -35° in CHCl2) exhibited n.m.r. peaks at δ0.68, 1.02 (methyl groups), δ1.18 (gem-dimethyl groups), δ3.83 (1 proton, narrow signal, 1β-H), δ3.6-4.3 (1 proton, broad signal, 3α-H) and δ5.57 (1-proton, multiplet, 6-H). The 3-monobenzoate thereof melts at 212°-216°; [α]D -20° in CHCl3).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[Cl:48][C:49]1[C:50]([O:61][CH3:62])=[C:51]([C:55]([O:59][CH3:60])=[C:56]([Cl:58])[CH:57]=1)[C:52](O)=[O:53].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:52](=[O:53])[C:51]3[C:55]([O:59][CH3:60])=[C:56]([Cl:58])[CH:57]=[C:49]([Cl:48])[C:50]=3[O:61][CH3:62])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: COc1c(Cl)cc(Cl)c(OC)c1C(=O)O
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1c(Cl)cc(Cl)c(OC)c1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3,5-dichloro-2,6-dimethoxybenzoic acid (9.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[C@@H:16]([OH:17])[C@@H:15]2[C@H:10]([CH2:11][CH2:12][C@:13]3([CH3:28])[C@@H:20]([C@@H:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH3:22])[CH2:19][CH2:18][C@H:14]32)[C@:9]2([CH3:29])[C@H:4]1[CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2.[CH3:31]C=O>>[CH3:31][O:26][C:25](=[O:27])[CH2:24][CH2:23][C@H:21]([C@@H:20]1[C@:13]2([CH3:28])[C@H:14]([C@H:15]3[C@H:10]([CH2:11][CH2:12]2)[C@:9]2([CH3:29])[C@@H:4]([CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2)/[C:3](=[CH:2]/[CH3:1])/[C:16]3=[O:17])[CH2:18][CH2:19]1)[CH3:22]
Reactant: CC=O
Reactant: CC[C@H]1[C@@H](O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Product: C/C=C1\C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
The present invention relates to a process for preparing obeticholic acid Form 1, wherein reacting 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester with CH3CHO to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester is carried out in a polar aprotic solvent at a temperature at about −50° C. to about −70° C. in the presence of BF3.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:19][N:11]2[C:12]3[C:17]([CH:18]=[C:10]2[CH2:9][C@H:8]1[CH2:20]OS(C)(=O)=O)=[CH:16][CH:15]=[CH:14][CH:13]=3)(=O)=O.[CH3:26][C@H:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[CH3:26][C@H:27]([N:34]1[CH2:6][C@@H:7]2[C@H:8]([CH2:9][C:10]3[N:11]([CH2:19]2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH:18]=3)[CH2:20]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)OC[C@@H]1Cc2cc3ccccc3n2C[C@H]1COS(C)(=O)=O
Solvent: CCO
Product: C[C@@H](c1ccccc1)N1C[C@H]2Cc3cc4ccccc4n3C[C@@H]2C1

Procedure:
A suspension of 11.0 g of trans-6,7,8,9-tetrahydro-7,8-bis[(methanesulphonyloxy)methyl]pyrido[1,2-a]indole [prepared as described in Example 14(iv)] in 60 ml of ethanol was treated with 26 ml of (S)-α-methylbenzylamine and heated to reflux for 18 hours. The cooled solution was concentrated and the precipitate was filtered off and purified by chromatography on silica gel using ethyl acetate/petroleum ether (2:1) for the elution. There were obtained 2.1 g of trans-2,3,3a,4,11,11a-hexahydro-2-[alpha(S)-methylbenzyl]-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indole, diastereomer A, of melting point 153° C., [α]D20 =+17.7° (CHCl3, c=0.51), and 1.6 g of trans-2,3,3a,4,11,11a-hexahydro-2-[alpha(S)-methylbenzyl]-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indole, diastereomer B, of melting point 154°-156° C.; [α]D20 =-54.2° (CHCl3, c=0.49).