Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]1[C:9]2=[N:10][C:11]3[C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([OH:18])=[C:8]2[C:7](=[N:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[O:6]1)[CH2:2][CH2:3][CH3:4].Cl.[OH2:30]>>[OH:18][C:17]1[C:16]2[C:11](=[C:12]([C:19]([F:22])([F:20])[F:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH:5]([OH:30])[CH2:1][CH2:2][CH2:3][CH3:4])[C:8]=1[C:7]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=[O:6]
Reactant: CCCCC1OC(=Nc2nccs2)c2c1nc1c(C(F)(F)F)cccc1c2O
Reactant: O
Agent: Cl
Product: CCCCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 50 °C

Procedure:
A mixture of 6.1 g of the product of Step C, 60 ml of water and 60 ml of 6N hydrochloric acid was heated at 50° C. for 5 hours and was then cooled to room temperature and iced and vacuum filtered. The product was washed with water and added to 100 ml of water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried, filtered and evaporated to dryness under reduced pressure. The 6.4 of residue was added to 50 ml of ether and the mixture was iced and vacuum filtered. The product was washed with ether and dried under reduced pressure at 60° C. to obtain 3.9 g of 4-hydroxy-2-(1-hydroxypentyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 190° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>C(O)C>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:34]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:35])=[CH:37][CH:38]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCOCC2)cn1
Reaction time: 18 h
Yield: 34.3 %

Procedure:
To a solution of morpholine (9.00 g, 103 mmol) in 400 mL ethanol was added N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.0 g, 52.2 mmol), 1-hydroxybenzotriazole (7.00 g, 51.8 mmol), and 6-aminonicotinic acid (6.00 g, 43.4 mmol). After stirring for 18 hours, the resulting solid was filtered. This was triturated with a mixture of 100 mL methanol and 100 mL dichloromethane to yield (6-Amino-pyridin-3-yl)-morpholin-4-yl-methanone (3.08 g, 14.9 mmol). MS (ESI) 208.1 (M+H)+.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=O.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cl-].[Zn+2].[Cl-].O1CCOCC1>[C:13]1([NH:19][N:20]2[C:1](=[O:12])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1Nc1ccccc1
Temperature: 25 °C
Yield: 30 %

Procedure:
Phthalic acid (1.66 gram, 0.01 mole), phenylhydrazine (1.08 gram, 0.01 mole), and zinc chloride (3.0 gram, 0.022 mole) were added into 50 ml. of dioxane. After refluxing for 2 hours, the mixture was cooled to room temperature. The solvent was then removed and the residue was poured into ice-water which precipitated a yellow solid. After recrystallization from methanol, the pure compound was obtained in 30% yield as yellow needles (0.7 grams; m.p. 180° C.).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)[C:12](Br)=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)[C:12]([C:39]3[CH:38]=[CH:37][C:36]([N:33]4[CH2:32][CH2:31][O:30][CH2:35][CH2:34]4)=[CH:41][CH:40]=3)=[CH:11][N:10]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 3, (R)-tert-butyl 3-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate with 4-morpholinophenylboronic acid to provide the title compound at 85% yield. 1H NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 7.36 (d, 2H), 6.92 (d, 2H), 5.16 (sb, 1H), 4.30-4.27 (m, 2H), 4.10-4.01 (m, 1H), 386-3.84 (m, 4H), 3.60-3.12 (m, 8H); 2.70-2.62 (m, 1H), 2.05-1.98 (m, 1H), 1.81-1.46 (m, 8H), 1.44 (s, 9H), 1.29-1.21 (m, 3H), 0.93 (d, 3H); MS (ESI) m/z: Found: 552.3 (M+1); Calc: 551.4 (M+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])O1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>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.O>[OH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: Brc1ccccn1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Oc1ccccc1-c1ccccn1
Yield: 80.1 %

Procedure:
9.5 g (˜43 mmol) of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 6.8 g (˜43 mmol) of 2-bromopyridine, 1.5 g (1.3 mmol) of Pd(PPh3)4, and 16 g (116 mmol) of K2CO3 were added to a 250 mL round bottle flask, along with a solvent mixture of 120 mL of dimethoxyethane and 150 mL of water. The mixture was heated to reflux for 24 hours under nitrogen. The reaction mixture was extracted with ethyl acetate and the organic phase was separated on silica gel column with 15% ethyl acetate as elute solvent. ˜5.9 g (yield ˜80%) of 2-(2-hydroxyphenyl)pyridine was obtained as a colorless liquid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Solvent: CC#N
Product: Fc1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1
Temperature: 200 °C
Yield: 97 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (Intermediate 2, 0.25 g, 0.97 mmol) was dissolved in anhydrous acetonitrile (3 mL) and 4-fluorobenzenamine was added (0.10 mL, 1.06 mmol). The mixture was heated at 200° C. for 600 s in a microwave (Emrys Optimizer model, Personal Chemistry). The solvents were removed under vacuum to give the desired product as a beige powder (0.313 g, 97%.).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][S:8]([CH2:11][S:12]([O-:15])(=O)=[O:13])(=[O:10])=[O:9].[Na+].Cl.CS([Cl:21])=O>P(Cl)(Cl)(Cl)=O>[CH3:7][S:8]([CH2:11][S:12]([Cl:21])(=[O:15])=[O:13])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)CS(=O)(=O)[O-]
Reactant: CS(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)CS(=O)(=O)Cl
Temperature: 70 °C

Procedure:
Phosphorus pentachloride (79.3 g, 0.381 mole) and sodium (methylsulfonyl)methanesulfonate (Formula II with Y=Na, X=H and R=CH3 ; 70 g, 0.359 mole) were stirred with 150 ml of phosphorus oxychloride. As the mixture was warmed to 70° C. in an oil bath, hydrogen chloride was slowly evolved, and the slurry thinned enough to be stirred with a magnetic stirrer. The mixture was heated for 18 hours in an oil bath at 80°-90° C., cooled, and filtered, and the residue was washed with dry chloroform. The chloroform caused the product to precipitate in the filtrate. The precipitate was collected, washed with a small amount of chloroform, and dried over sodium hydroxide pellets: yield, 28.5 g (41%); mp 109°-111° C.; MS (direct-probe temperature, 20° C.) m/e 193 (M+H), 192 (M), 177 (M-CH3), 157 (CH3SO2CH2SO2), 143, 141, 113 (CH2SO2Cl), 98 (CH3SOCl), 94, 93 (CH3SO2CH2), 79 (CH3SO2), 78, 64, 63 (CH3SO); IR (cm-1, strong and medium bands) 3045, 3025, 2995 s, 2930 s, 1405, 1390 s, 1380 s, 1360, 1335 s, 1325 sh, 1315 s, 1225, 1175 s, 1160 s, 1110 s, 980 s, 965, 860 s, 760 s, 695, 595 s, 515 s, 495 s, 460 s.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH3:24])[CH3:14]>>[CH2:16]([N:15]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:23][CH3:24]
Reactant: CCCCCCCCCC1CO1
Reactant: CCNCCCCCCNCC
Product: CCCCCCCCCC(O)CN(CC)CCCCCCN(CC)CC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and N,N'-diethylhexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-ethyl-2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = CH3CH2, X = (CH2)6, Z = H).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.Cl[C:12]([O:14][CH2:15][Cl:16])=[O:13].C(N(CC)CC)C>O1CCCC1>[C:12](=[O:13])([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[O:14][CH2:15][Cl:16]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(Cl)OCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCCl)Oc1ccc([N+](=O)[O-])cc1
Yield: 94.2 %

Procedure:
p-Nitrophenol (100 g, 0.72 moles) was dissolved in anhydrous tetrahydrofuran (3 L) and stirred vigorously. To this solution was added chloromethyl chloroformate (70 mL, 0.79 moles) at room temperature followed by triethylamine (110 mL). After stirring for 1 hour, the reaction mixture was filtered and the filtrate was concentrated and then diluted with ethyl acetate (1 L). The organic solution was washed with 10% potassium carbonate (3×500 mL) and 1N HCl (2×300 mL), brine (2×300 mL) and dried over anhydrous sodium sulfate. Removal of the solvent gave 157 g (95%) of the title compound (52) as a solid. The compound was unstable to LC-MS. 1H NMR (CDCl3, 400 MHz): 5.86 (s, 2H), 7.44 (d, J=9 Hz, 2H), 8.33 (d, J=9 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([CH2:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH2:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[F:20][C:17]([F:18])([F:19])[C:15](=[CH2:16])[CH2:14][C:11]1([OH:21])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C=C(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=C(CC1(O)CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl-4-hydroxy-4-(2-(trifluoromethyl)allyl)piperidine-1-carboxylate 17B (300 mg, 0.97 mmol), in DCM (5 mL) was added a solution of HCl in dioxane (3 M, 1 mL, 3 mmol), and then the mixture was stirred at room temperature for 16 hrs. The mixture was concentrated in vacuo to get the desired compound which was used directly for the next step. LC-MS: m/z 210.2 (M+H)+
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]1=O)[CH3:4].[CH3:26][NH:27][NH2:28]>CO>[ClH:1].[CH3:2][N:3]([CH3:4])[CH2:5][C:6]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[CH:8]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:27]([CH3:26])[N:28]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CN(C)CC1(c2ccccc2)CCCC(=Cc2ccccc2)C1=O
Reactant: CNN
Agent: Cl
Solvent: CO
Product: CN(C)CC1(c2ccccc2)CCCC2C1=NN(C)C2c1ccccc1
Yield: 36.4 %

Procedure:
A solution of 10.7 g of 2-[(dimethylamino)methyl]-2-phenyl-6-(phenylmethylene)cyclohexanone, monohydrochloride in 70 ml of methanol is treated with 1.5 g of methylhydrazine and the resulting solution is refluxed for 4 hours. The solution is cooled and the solvent is removed on a rotary evaporator to give 13.7 g of a semi-crystalline solid residue, which is crystallized from 30 ml of isopropanol to give 4.2 g of the title compound, melting point 225°-227° C (dec.). An additional 0.77 g of product is recovered from the filtrate giving a total yield of 4.97 g of the title compound, melting point 225°-227° C. Recrystallization of 5.6 g of this material from 100 ml of isopropanol gives 4.8 g of product, melting point 225°-227° C (dec.).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH3:19])=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[OH:11])([O:3][CH2:4][CH3:5])=[O:2].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[C:1]([C:6]1[NH:7][C:8]([CH3:19])=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[O:11][CH2:20][CH:22]1[O:24][CH2:23]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1[nH]c(C)c(Cc2ccccc2)c1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1[nH]c(C)c(Cc2ccccc2)c1OCC1CO1
Yield: 61.7 %

Procedure:
Using the method described in Example V, 20 g of 2-carboethoxy-3-hydroxy-4-benzyl-5-methyl-pyrrole, 14 g of epibromohydrin and 20 g of dry potassium carbonate in 150 ml of methyl isobutyl ketone give 15 g of 1-(2-carboethoxy-4-benzyl-5-methyl-pyrrol-3-oxy)-2,3-epoxypropane as a pale yellow, very viscous oil.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH3:28])[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=1[O:27][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:20])=[O:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(I)cc1
Reactant: Cc1ccccc1O
Product: Cc1ccccc1Oc1ccc(C(=O)Nc2ccccc2C(=O)O)cc1

Procedure:
In analogy to example 2,2-(4-o-Tolyloxy-benzoylamino)-benzoic acid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3] and o-cresol. MS (m/e): 346.1 (M−H−, 100%).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:19])[C:9]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:5][C:6]1[CH:7]=[C:8]([O:19][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:9]([C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:18]=2)=[N:10][C:11]=1[CH3:12]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(-c2ncccn2)nc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ncccn3)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Dimethyl sulfoxide (2.5 ml) was added to 5,6-dimethyl-2-pyrimidin-2-yl-pyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (167 mg), and cesium carbonate (243 mg), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (54 mg, yield 55%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH3:30])=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone, was treated with acetylchloride (1.05 eq) and triethylamine (1.05 eq) in CH2Cl2 under argon at RT for 2 h to give after purification by prep. HPLC the title compound.
Reaction SMILES: O1[C:3]23[C@:19]([CH3:24])([CH2:20][CH2:21][C:22](=[O:23])[CH:2]12)[C@@H:18]1[C@H:6]([C@H:7]2[C@:15]([CH3:25])([CH2:16][CH2:17]1)[C@@H:10]([C@H:11]([CH3:14])[CH2:12][OH:13])[CH2:9][CH2:8]2)[CH2:5][CH2:4]3.[N-:26]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].S(=O)(=O)(O)O>CS(C)=O>[NH2:26][C:2]1[C:22](=[O:23])[CH2:21][CH2:20][C@@:19]2([CH3:24])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:25])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C@H:11]([CH3:14])[CH2:12][OH:13]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A solution of (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one (7.7 mmole) in dimethyl sulfoxide (40 mL), under a nitrogen atmosphere, was placed in an oil bath heated at 60° C. The solution was stirred vigorously as sodium azide (8.11 g, 0.338 mole) was slowly added. After the addition of the azide was complete, concentrated sulfuric acid (0.54 mL) was added. The bath temperature was raised to 100° C. and the reaction was stirred at this temperature for 90 minutes. The reaction was removed from the oil bath and cooled to room temperature and the resulting solid mass was broken up and poured into cold water (550 mL). The mixture was stirred for 30 min and the solids were collected by filtration, washed with water and dried to a yellow solid. The crude product was purified by flash chromatography (hexane-30% ethyl acetate) to give (20S)-4-amino-21-hydroxy-20-methylpregna-4,6-dien-3-one. IR 3462, 3390, 3346, 1652, 1616, 1592, 1564 cm-1 ; MS (CI) m/z 344 (100%, M+ +1); (EI) m/z 343 (60%, M+), 150 (100%); 1H NMR (CDCl3) δ 0.76 (3H, s, C18 -Me), 1.04+1.05 (6H, s+d, C19 -Me+C21 -Me) 2.48 (1H, dq), 2.63 (1H, dq), 3.38 (1H, dd, 1/2 C21 -CH2), 3.64(dd+v br, 1/2 C21 -CH2 +NH2), 5.97 (1H, dd) 6.30 (1H, dd); 13C NMR (CDCl3) δ 121.77, 132.08, 132.98, 136.55, 194.40.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:28](OC(=O)C)(=[O:30])C>Cl(O)(=O)(=O)=O.C(O)=O>[CH:28]([O:25][C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[C@H:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:27])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24]1)=[O:30]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O=CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 40 °C

Procedure:
Ten grams of lithocholic acid was dissolved in 40 ml. of 89.9% formic acid and 8 drops of 70% perchloric acid, and the resulting solution heated to 55° C. with stirring. The solution was then cooled to 40° C. at which time 35 ml. of acetic anhydride was slowly added and the temperature of the reaction mixture maintained between 55°-60° C. The solution was cooled and poured into 500 ml. of water and the resulting precipitate was filtered, washed with water and dried to yield 3α-formyloxy-5β-cholan-24-oic acid.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH:14](O)[CH:15]=[CH2:16])[CH:11]=[CH:12][CH:13]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:19])([F:18])[F:6])[CH:9]=1)[CH:15]=[CH2:16]
Reactant: C=CC(O)c1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC(Cl)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
Dimethylformamide (5 mL) was added to a solution of 1-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol (50 g) in dichloromethane (500 mL) at 0 to 5° C. The reaction mixture was stirred for 5-10 min at room temperature. The reaction mixture was cooled at 0 to 5° C. and thionyl chloride (44.26 g) was added slowly maintaining the temperature at 0 to 5° C. The reaction mixture was stirred at 0 to 5° C. for 1-2 hours. After completion of the reaction, the mixture was quenched slowly with ice-chilled de-ionized water (250 mL) at 0-10° C. and stirred for additional 30 minutes at 0 to 5° C. Organic Layer was separated, washed twice with a solution of sodium chloride (10%; 250 mL) and concentrated under vacuum at 40° C. to 45° C. to give 1-(1-chloroprop-2-en-1-yl)-3-(trifluoromethyl)benzene.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[C:38]#[N:39].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:42]=[CH:41][CH:40]=[C:37]([C:38]#[N:39])[CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: N#Cc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (90.4 mg, 0.20 mmol), 3-bromo-benzonitrile (37.5 mg, 0.21 mmol), and Pd[P(Ph)3]4 (15.9 mg, 6.9 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 11.7 mg. MS: 426.1 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 1.80-2.04 (m, 3H), 2.15-2.36 (m, 1H), 3.39-3.58 (m 2H), 4.32-4.43 (m, 1H), 4.89-5.14 (m, 2H), 7.03-8.07 (m, 13H), 10.13-10.20 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][N:36]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(-c3csc(C4CCNCC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(c2nc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cs2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 28.2 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(2-piperidin-4-yl-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.17 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (15 μL, 0.19 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile to provide 28 mg (28%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 8.38 (s, 1 H), 8.10 (s, 1 H), 7.83 (d, 1 H), 7.67 (s, 1 H), 7.27-7.40 (m, 5H), 7.17-7.24 (m, 2 H), 5.66 (s, 2 H), 3.59-3.69 (m, 2 H), 3.16-3.28 (m, 1 H), 2.85-2.95 (m, 5H), 2.20 (d, 2 H), 1.78 (q, 2 H); ES-MS m/z 585.21 [M+H]+, HPLC RT (min) 2.97.