Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][CH2:37][NH:38][C:15]2[N:14]=[C:13]([C:11]3[S:10][C:9]4[CH:21]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:6]=[CH:7][C:8]=4[CH:12]=3)[C:18]([CH3:19])=[CH:17][N:16]=2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Reactant: CNC(=O)c1ccc2cc(-c3nc(Cl)ncc3C)sc2c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C(=O)OC(C)(C)C)CC4)ncc3C)sc2c1
Temperature: 95 °C
Yield: 43.9 %

Procedure:
A mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methylamide (263 mg, 0.830 mmol), 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester (358 mg, 1.47 mmol) and diisopropylethylamine (0.44 mL) in 1,4-dioxane (10 mL) is heated at 95° C. for 20 hours. The solvent is removed after cooling and the residue is subjected to chromatography on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 0-10%, to give 4-{3-[5-methyl-4-(6-methylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (191 mg, 44% yield). The intermediate is dissolved in THF (8 mL) and 5 N hydrochloric acid (5 mL) is added. The solution is heated at 70° C. for 4.5 hours and then cooled before evaporating the solvent. Methanol is added to the residue and the mixture is sonicated for 30 minutes. The solid is filtered and washed with diethyl ether, then dried in a vacuum oven at 50° C. for 18 hours to give the title compound (129 mg, 66% yield). ES+(m/z) 425 [M(free base)+H].
Reaction SMILES: CO[C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[N:11]1([C:3]([C@H:4]2[NH:5][C:6](=[O:9])[CH2:7][CH2:8]2)=[O:10])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: O=C1CC[C@@H](C(=O)N2CCOCC2)N1

Procedure:
L-pyroglutamic acid methyl ester (23.91 g, 177 mmol), morpholine (21.8 g, 250 mmol) and 4-dimethylaminopyridine (0.2 g, 1.64 mmol) are heated under reflux in toluene (130 ml) for 12 hours. The product precipitates as an oil. The oil is separated from the toluene, diluted with dichloromethane (100 ml) and washed successively with 0.1 M HCl, 0.1 M NaOH and water (50 ml each). The dichloromethane phase is concentrated to obtain a suspension, which is filtered yielding the crude product. The crude product is dissolved in THF (200 ml) at 45° C. and, upon cooling in an ice bath, (S)-5-morpholine-4-carbonyl)pyrrolidin-2-one precipitates as white crystals. Enantiopurity (GC) 88.7% (S)-Enantiomer.
Reaction SMILES: C(O[C:6]([NH:8][N:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:35])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])C(O)=O>C(Cl)Cl>[CH3:22][O:21][C:19]([C:18]1[N:9]([NH:8][C:6](=[O:7])[C:37]([F:42])([F:41])[F:36])[C:10](=[O:35])[C:11]2[C:16]([C:17]=1[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:20]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NC(=O)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of the compound obtained in Example 67 (5.60 g) in methylene chloride (15 ml) is added trifluoroacetic acid (15 ml), and the mixture is allowed to stand at room temperature for three hours. After the reaction is complete, the reaction mixture is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, and extracted. The extract is washed, dried, and concentrated under reduced pressure. The resulting residue is crystallized from ethyl acetate to give 3-methoxycarbonyl-2-(trifluoroacetyl-amino)-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone as listed in Table 24.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11]([C:13]1[S:17][C:16](/[CH:18]=[CH:19]/[C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:15][C:14]=1[CH3:32])=O>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:11]([C:13]1[S:17][C:16](/[CH:18]=[CH:19]/[C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:15][C:14]=1[CH3:32])=[O:10])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(/C=C/c2c(-c3ccccc3)noc2C)nc1C
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1nc(/C=C/c2c(-c3ccccc3)noc2C)sc1C(=O)NC(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a stirred solution of isopropylamine (56 mg, 0.95 mmol) in dioxane (2 mL) under argon and at room temperature was added trimethylaluminium (0.47 mL of a 2M solution in toluene, 0.94 mmol). After 1 h, a solution of 4-methyl-2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid methyl ester (80 mg, 0.24 mmol) in dioxane (2 mL) was added and the reaction mixture warmed to 90° C. After 24 h, the reaction mixture was cooled, quenched with ice and Seignettes's salt solution, then extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 10 to 80% ethyl acetate in heptane) gave the title compound (40 mg, 46%) as an off white solid. MS: m/e=368.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(O)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)ccc([N+](=O)[O-])c1O
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-hydroxy-2-methylbenzoic acid (5.00 g, 25.3 mmol) in concentrated H2SO4 (98%, 10 mL) was added concentrated HNO3 (63%, 10 mL) dropwise. The mixture was stirred at −40° C. for 10 min. The mixture was poured into ice-water and extracted by EA (3 times). The organic layers were combined, dried over anhydrous Na2SO4. Then the solvent was evaporated in vacuo to afford 3-hydroxy-2-methyl-4-nitrobenzoic acid as a yellow solid, which was used for next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:24]([F:25])=[C:23]([NH2:26])[C:9]2[C:10](=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:27])(=[O:3])[CH3:2].Cl.[CH3:29][N:30]([CH3:37])[CH2:31][CH2:32][CH2:33][C:34](O)=[O:35].Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[C:24]([F:25])=[C:23]([NH2:26])[C:9]2[C:10](=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][N:30]([CH3:37])[CH3:29])=[C:16]([F:21])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCCN(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.5 %

Procedure:
To a solution of 7-(acetoxymethyl)-5-amino-2-[4-amino-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (500 mg, 1.32 mmol) in dimethylformamide (15 mL) were added 4-dimethylaminobutyric acid hydrochloride (3.06 g, 16.9 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.23 g, 16.9 mmol), and the mixture was stirred at room temperature for 2.5 hours. Water was added thereto, and the mixture was extracted with ethyl acetate. Purification by silica gel column chromatography (9:1 chloroform/methanol) gave 1j (386 mg, 60%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[S:25][C:26]([CH:29]=O)=[CH:27][N:28]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:29][C:26]2[S:25][C:24]([NH:23][C:13]3[CH:14]=[CH:15][C:16]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:11]([O:10][CH3:9])[CH:12]=3)=[N:28][CH:27]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(CNc3ccc(F)cc3)s2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
21 mg (0.19 mmol) 4-Fluoroaniline was dissolved in tetrahydrofurane (1 ml). 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde was added. The suspension was stirred at room temperature for 10 minutes. 133 mg (0.56 mmol) sodium triacetoxyborohydride and 23 mg (0.38 mmol) acetic acid were added and the reaction was stirred at room temperature over night. Since the reaction was not complete the same amount of 4-fluoroaniline, sodium triacetoxyborohydride and acetic acid were added and the reaction stirred at room temperature over night. 2N aqueous NaOH solution was added and the reaction was extracted once with methylene chloride. The organic layer was washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified on silica gel with ethyl acetate yielding 22 mg (26%) [5-(4-fluoro-benzyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 410.1 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.63 (s, 1H), 7.28-7.16 (m, 4H), 6.95-6.87 (m, 4H), 6.66-6.60 (m, 2H), 4.39 (s, 2H), 3.85 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].[NH4+].[OH-]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:14])([F:16])[F:15]
Reactant: N#CCc1ccc(F)c(OCC(F)(F)F)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCc1ccc(F)c(OCC(F)(F)F)c1

Procedure:
800 mg (10 mmol) of borane-methyl sulfide complex were added to a solution of 1.23 g (5.27 mmol) of [4-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetonitrile in 50 ml of dry tetrahydrofuran. The reaction mixture was refluxed for 4 hours. Solvent was removed and then water was added. A first extraction with diethyl ether allowed to partially purify the crude reaction mixture. The resulting aqueous layer was then basified with NH4OH, and the product was extracted with dichloromethane. After removal of the solvent 1 g (80% yield) of the title compound was isolated as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([O:26][CH3:27])[CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:19]([O:26][CH3:27])[CH:18]=1
Reactant: Ic1ccncc1NCC1CCCCO1
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1ccncc1NCC1CCCCO1

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-N-((tetrahydro-2H-pyran-2-yl)methyl)pyridin-3-amine and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 3.5 hours at reflux. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) followed by EtOAc:MeOH (100:0 to 90:10). Brown oil (103%). MS (ESI): m/z=317.167 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([F:24])[CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: OB(O)c1ccnc(F)c1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccnc(F)c4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoropyridine-4-boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.74 min; Mass spectrum (ESI+): m/z=400 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([N+:35]([O-])=O)[CH:29]=3)[C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:38](O)=O>[Pd]>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]4[NH:34][CH:38]=[N:35][C:30]=4[CH:29]=3)[C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CO
Reactant: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2ccc(C3CCCCC3)cc2)CC1
Agent: [Pd]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc(C3CCCCC3)cc2)CC1

Procedure:
Prepared from 4-cyclohexyl-N-[1-((4-amino-3-nitrophenyl)-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxoethyl]-benzenesulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])(=O)C.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([S:8]([CH2:7][CH2:6][CH2:5][OH:4])(=[O:9])=[O:10])[CH2:15][CH2:14]1
Reactant: CC(=O)OCCCS(=O)(=O)Cl
Reactant: CN1CCNCC1
Product: CN1CCN(S(=O)(=O)CCCO)CC1

Procedure:
Using 3-acetoxypropane-1-sulfonyl chloride and 1-methylpiperazine, the same reaction as in Reference Example 44 and 46 was conducted to produce the title compound. m.p. 90°-93° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=2[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[C:24]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:15][CH3:16])=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1)#[N:25]
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(=O)O)nc(C#N)c2c(Oc3ccccc3)cccc12
Yield: 92.7 %

Procedure:
To a mixture of 1-cyano-4-methoxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (727 mg, 2.18 mmol) and methanol/tetrahydrofuran (12.5 mL, 1:1.5) was added 2N sodium hydroxide (5.4 mL, 10.89 mmol) at room temperature. The yellow solution was stirred at that temperature for seventy minutes before it was concentrated. Water (20 mL) was added and the mixture was adjusted to pH=2 with 1N HCl (13 mL). The mixture was then extracted with dichloromethane and ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo to give the title compound as a yellow solid (647 mg): MS: (+) m/z 320.80 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[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(O)=O>[OH:25][C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[CH:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:15]2[CH2:14][C@H:13]([OH:27])[C@@:12]2([CH3:28])[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
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]3C[C@H](O)[C@]12C
Solvent: O=CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 15 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
A dispersion of deoxycholic acid (1030 g; 2.63 mol) in 98% formic acid (3.72 l) was heated at 60°-70° with stirring for 2 hr. The resulting solution was allowed to cool slowly and was then left at room temperature overnight. It was then concentrated by distillation in vacuo at 40°. After 2 liters of distillate was collected, crystallization began to occur and the mixture was cooled to 15° C. The solids were then collected by filtration, washed with cold formic acid (400 ml) and dried to give 1065 g (90.5%) of 3α,12α-dihydroxycholanic acid, diformate, mp 192°-194°. Concentration of the mother liquors afforded additional material which raised the yield to about 95%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[O:22]1[C:24]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[OH:22][C:24]1([CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCCC2(CCC1)CO2
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2(O)CCCCCCC2)c1
Temperature: 120 °C

Procedure:
A suspension of the phenol 58 (1.0 g, 3.5 mmol), 1-oxa-spiro[2.7]decane (0.5 g, 3.2 mmol) and Cs2CO3 (1.14 g, 3.5 mmol) in DMSO (4 mL) was heated at 120° C. for 16 h. After completion of reaction, the mixture was quenched by the addition of 1N HCl and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (0 to 10% 7N NH3/methanol—CH2Cl2) afforded 2-(3-(3-((1-hydroxycyclooctyl)methoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (1.057 g, 72%): 1H NMR (400 MHz, CDCl3) δ 7.10-7.36 (m, 2H), 6.40-6.80 (m, 6H), 3.69 (s, 2H), 2.10-2.45 (m, 2H), 1.30-2.0 (m, 18H).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:17]2[C:16](=[O:27])[N:15]([CH2:28][CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C:14](=[O:39])[N:13]([CH3:40])[C:12]=2[N:11]=1>C1COCC1.O>[Si:32]([O:31][CH2:30][CH2:29][CH2:28][N:15]1[C:16](=[O:27])[C:17]2[N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:10]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:11][C:12]=2[N:13]([CH3:40])[C:14]1=[O:39])([C:35]([CH3:36])([CH3:37])[CH3:38])([CH3:33])[CH3:34]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(OC1CCCC1)n2Cc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Step 1 Cyclopentanol (0.21 mL, 2.31 mmol) was dissolved in THF (5 mL) and sodium hydride (60% in oil, 0.092 g, 2.31 mmol) was added. The reaction was stirred for 1 h. 8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, intermediate 77) was added and the reaction was stirred at room temperature for 15 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to give 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 100% yield) as a golden oil. LCMS retention time=5.843 min and 71% purity, LCMS MH+ 547.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[F:32][C:33]1([F:40])[CH2:35][CH:34]1[CH:36]=[CH:37][C:38]#[N:39]>C(#N)C>[F:32][C:33]1([F:40])[CH2:35][CH:34]1[CH:36]([N:15]1[CH:14]=[C:13]([C:11]2[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:12]=2)[CH:17]=[N:16]1)[CH2:37][C:38]#[N:39]
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: N#CC=CC1CC1(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4(F)F)c3)n2)cn1
Temperature: 50 °C
Reaction time: 24 h
Yield: 54.1 %

Procedure:
To a mixture of 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (200 mg; 0.754 mmol) and DBU (56 μL; 0.37 mmol) in acetonitrile (10 mL) was added 3-(2,2-difluorocyclopropyl)acrylonitrile (0.75 mmol). The mixture was stirred in a sealed vial at 50° C. for 24 hours. Further 3-(2,2-difluorocyclopropyl)acrylonitrile (0.4 mmol) was added and the mixture was stirred for a further 24 hours at 50° C. The solvent was removed under reduced pressure and the material was purified on silica gel, eluting with methylene chloride/6% ammonium hydroxide in methanol (50:1 to 15:1) to give 3-(2,2-difluorocyclopropyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (160 mg) as a mixture of diastereoisomers. MS (apci) m/z=395.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([CH3:20])=[CH:15][N:14]=1.CO>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[NH:7][C:6]=3[CH:11]=2)[C:16]([CH3:20])=[CH:15][N:14]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Solvent: O
Solvent: CO
Product: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 71 %

Procedure:
To a vial with 5-aminobenzo[d]oxazol-2(3H)-one (300.1 mg, 2.0 mmol) and 2,4-dichloro-5-methylpyrimidine (423.8 mg, 2.6 mmol), MeOH (8 mL) and H2O (2 mL) were added. The turbid mixture was stirred at room temperature for 64 h. Precipitate from reaction mixture was collected by filtration, washing with EtOAc (3 mL×2), and was further dried in vacuo. 5-(2-Chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one was obtained as an off-white solid: 394 mg (71% yield); 1H NMR (300 MHz, DMSO) δ 11.68 (br s, 1H), 8.62 (s, 1H), 7.94 (d, J=0.8, 1H), 6.97 (d, J=2.0, 1H), 6.82 (d, J=8.1, 1H), 6.74 (dd, J=2.0, 8.1, 1H), 2.15 (s, 3H); LCMS (M+) m/z 277.10.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12]2[N:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:28][C:29]1[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])[CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH:28][C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])[CH:32]=[CH:33][CH:34]=3)[N:17]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)N(c1ncnc(Cl)n1)CCC2
Reactant: C=CC(=O)Nc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Nc2ncnc(N3CCCc4ccc(Cl)cc43)n2)c1
Temperature: 100 °C

Procedure:
To a slurry of 7-chloro-1-(4-chloro-[1,3,5]triazin-2-yl)-1,2,3,4-tetrahydro-quinoline (Step 2)(70 mg, 0.249 mmol) in IpOH (2.0 ml) was added DIEA (0.20 mL, 1.15 mmol) and N-(3-aminophenyl)acrylamide (100 mg, 0.192 mmol). The heated at 100° C. for 18 h, then cooled to RT. The organics were concentrated under reduced pressure then purified by column chromatography (elution with CH2Cl2 followed by 99:1 CH2Cl2/MeOH followed by 97:3 CH2Cl2/MeOH) to give N-{3-[4-(7-chloro-3,4-dihydro-2H-quinolin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide: MS m/z=407 [M+H]+. Calc'd for C21H19ClN6O: 406.13.