Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15](C)[NH:16][C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[CH3:13][N:15]1[C:24]2[C@:23]3([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]([CH2:21][CH2:22]3)[C:19]=2[C:17](=[O:18])[NH:16]1
Reactant: CN(NC(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1[nH]c(=O)c2c1[C@@]1(C)CC[C@@H]2C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
Trifluoroacetic acid (15.7 mL) was added to a solution of N-methyl-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (6.13 g, 18.9 mmol) in dichloromethane (15.7 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, at room temperature for 1 h, and then heated at reflux for 6 h. Following overnight stirring at room temperature, the solvent was evaporated. The residue was taken up in dichloromethane (100 mL) and washed with water (2×100 mL) and brine (100 mL), dried (sodium sulfate), filtered, evaporated and purified using a Biotage system eluting with 2% methanol/dichloromethane to give (4R,7S)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (2.46 g, 63%) as a white solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[C:18](=[O:37])[N:17]2[C:38](OC2C=CC([N+]([O-])=O)=CC=2)=[O:39])=[CH:12][CH:11]=1)#[N:9]>C(#N)C>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)[C:18](=[O:37])[N:17]2[C:38]([NH:7][CH:4]2[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)=[O:39])=[CH:14][CH:15]=1)#[N:9]
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: NC1CCSCC1
Solvent: CC#N
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrahydro-2H-thiopyran-4-amine (76 mg, 0.65 mmol) is added to a solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 220 mg, 0.32 mmol) in acetonitrile (6 mL), and the mixture is stirred at room temperature for 30 min and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 168 mg; ESI mass spectrum [M+H]+=555; Retention time HPLC: 1.19 min (Z018_S04).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc(C2CCNCC2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylate (2 g, 6.06 mmol) in DCM (2 mL) was added TFA (3 mL). The solution was stirred at room temperature for 30 min. The reaction solution was concentrated to afford 2,6-dichloro-4-(piperidin-4-yl)pyridine as TFA salt, which was used without further purification. LCMS (ESI) [MH]+=231.1.
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pt]=O.C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCCN1CC#CCN1CCCC1
Agent: O=[Pt]
Solvent: CCO
Product: O=C1CCCN1CCCCN1CCCC1

Procedure:
A solution containing 21.0 g. (0.10 mole) of 1-(4-pyrrolidino-2-butynyl)-2-pyrrolidinone dissolved in 205 ml. of absolute ethanol was hydrogenated in a bottle-type hydrogenator over 0.6 g. of platinum oxide catalyst. When the theoretical quantity of hydrogen was absorbed, the catalyst was removed by filtration and the filtrate was removed under reduced pressure. Upon distllation, the product, N-[4-(1-pyrrolidinyl)-butyl]-2-pyrrolidinone, was obtained as a clear oil boiling at 118° C. at 0.05 mm.; ND25 = 1.4922.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][NH2:12]>O1CCOCC1>[CH2:1]([NH:8][C:9](=[S:10])[NH:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: S=C=NCc1ccccc1
Solvent: C1COCCO1
Product: NNC(=S)NCc1ccccc1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
Benzylisothiocyanate (4.0 g) is slowly added to 1.8 g of anhydrous hydrazine in 50 ml dioxane. The reaction mixture is stirred at room temperature, the dioxane is then removed in vacuo and the residue is recrystallised from ethanol to give 4-benzylthiosemicarbazide as a crystalline solid (2.5 g), m.p. 127.6° C.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[C:87]([O:91][C:92]([N:94]1[CH2:98][C:97]([F:100])([F:99])[CH2:96][C@H:95]1[C:101]([OH:103])=O)=[O:93])([CH3:90])([CH3:89])[CH3:88]>>[C:87]([O:91][C:92]([N:94]1[CH2:98][C:97]([F:99])([F:100])[CH2:96][C@H:95]1[C:101]([NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:103])=[O:93])([CH3:88])([CH3:89])[CH3:90]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)[C@@H]3CC(F)(F)CN3C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-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 following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-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, except (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 763.5 (M+H)+, 2.55 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.46 (br. s., 1H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.72 (s, 1H), 4.63 (br. s., 1H), 4.50 (d, J=9.2 Hz, 1H), 3.84 (br. s., 1H), 3.72 (td, J=6.7, 13.4 Hz, 1H), 2.84 (br. s., 1H), 2.55 (d, J=13.4 Hz, 1H), 2.51-2.37 (m, 2H), 2.12 (dd, J=6.4, 17.1 Hz, 1H), 1.96 (br. s., 1H), 1.73 (br. s., 1H), 1.70 (s, 4H), 1.61 (br. s., 2H), 1.56 (br. s., 9H), 1.53-1.45 (m, 5H), 1.45-1.37 (m, 3H), 1.36-1.29 (m, 2H), 1.28-1.23 (m, 1H), 1.17-1.09 (m, 2H), 1.08 (s, 3H), 1.02 (s, 6H), 0.94 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][N:10]([CH3:25])[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[C:16]2[S:21](Cl)(=[O:23])=[O:22]>>[CH3:9][N:10]([CH3:25])[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[C:16]2[S:21]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:23])=[O:22]
Reactant: Cc1noc(N)c1Br
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Product: Cc1noc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c1Br
Yield: 68 %

Procedure:
5-Dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)-1-naphthalenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 5-dimethylaminonaphthalenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 87°-89° C., yield 68%.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[N:3]=1.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[N:3]=1
Reactant: C[O-]
Reactant: Cc1cc(C#Cc2cn(-c3cncc(Cl)n3)c(C)n2)ccn1
Agent: [Na+]
Solvent: CO
Product: COc1cncc(-n2cc(C#Cc3ccnc(C)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=306.5 (M+H+) was prepared by treatment of 100 mg 0.32 mmol) 2-chloro-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrazine (27) with 5 equiv. of sodium methoxide in 4 ml of methanol (3 h, 55° C.). The compound, after extraction with ethyl acetate/water, was purified by chromatography. Yield: 62 mg (0.203 mmol, 63%).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10]([NH2:12])=[N:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(OC)(O[CH3:18])(=O)=O>>[C:1]1([N:7]2[CH2:11][C:10](=[NH:12])[N:9]([CH3:18])[C:8]2=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NC(=O)N(c2ccccc2)C1
Reactant: COS(=O)(=O)OC
Product: CN1C(=N)CN(c2ccccc2)C1=O
Temperature: 160 °C

Procedure:
To 0.4 g. of 1-phenyl-4-amino-2-oxo-3-imidazoline was added 1 ml. of dimethyl sulfate. This mixture was slowly heated to 160° C., over a 45-minute period. The reaction mixture was put onto the vacuum pump and warmed to 90° C. to remove excess dimethyl sulfate. To the reaction was added 10 ml. of absolute alcohol giving a white solid. This material, 400 mg., was filtered and dried. This solid material was then added to water where it rapidly dissolved giving an acidic solution. This indicates the desired compound had precipitated from ethanol as the methyl sulfuric acid salt. Addition of 5N sodium hydroxide precipitated the desired product; after filtering and drying, 260 mg. (61%) of 1-phenyl-4-imino-3-methyl-2-oxoimidazolidine was obtained. This material was then recrystallized from acetone to give pure product, m.p. 156°-158° C. The mass spectrum of the compound gave a parent peak at m/e 189.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27]([OH:29])=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[N:33]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:32]C1.F[P-](F)(F)(F)(F)F.CN.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:32][NH:33][C:27]([C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:10])[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:29]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2cccnc2c(C(=O)O)c1-c1ccccc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccccc2)c(C(C)NC(=O)OC(C)(C)C)nc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1-(tert-butoxycarbonylamino)ethyl)-3-phenyl-1,5-naphthyridine-4-carboxylic acid (205 mg, 0.52 mmol) in DMF (5 mL) was added PyBop (407 mg, 1.5 mmol), methanamine (0.52 mL, 2.0 eq) and N-ethyl-N-isopropyl-propan-2-amine (0.18 mL, 2.0 eq). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between water (10 mL) and EtOAc (15 mL). The water layer was extracted with EtOAc (5 mL×2). The combined organics were washed with water (10 mL×2), 0.5 N NaOH (5 mL×2), water (5 mL×2), brine (5 mL) and dried over sodium sulfate. Removal of solvents followed with column chromatography on silica gel (EtOAc/hexane, up to 2/1) to give a white solid. Mass Spectrum (ESI) m/e=407 (M+1).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([C:19]1[N:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:22]=[C:21]([CH:28]=O)[CH:20]=1)[CH2:17][CH3:18]>>[C:24]([N:23]1[C:19]([CH2:16][CH2:17][CH3:18])=[CH:20][C:21]([CH2:28][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[N:22]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Product: CCCc1cc(CNCCN2CCN(c3ccccc3)CC2)nn1C(C)(C)C
Yield: 64.2 %

Procedure:
Compound 3 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][NH2:21].CO.[BH4-].[Na+].[ClH:26].C(=O)([O-])O.[Na+]>CO>[ClH:26].[ClH:26].[CH3:20][NH:21][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:9]=1
Reactant: CN
Reactant: O=Cc1cn(-c2ncccn2)c(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cn(-c2ncccn2)c(-c2ccccc2)n1
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a solution of 2-phenyl-1-pyrimidin-2-yl-1H-imidazole-4-carbaldehyde (150 mg) in methanol (15 mL) was added 40% methylamine-methanol solution (233 mg) and the mixture was stirred for 10 min. Sodium borohydride (68 mg) was added and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid was added to the reaction mixture and the mixture was stirred for 30 min. The mixture was neutralized with saturated sodium hydrogen carbonate solution, and extracted with tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:ethyl acetate-methanol=19:1→7:3) and dissolved in methanol (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. Tetrahydrofuran was added to the residue, and insoluble materials were collected by filtration to give the title compound as a colorless powder (yield 55 mg, yield 27%).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:11]([OH:19])(=[O:18])[C:12]([CH2:14][C:15](O)=[O:16])=[CH2:13]>[OH-].[Na+]>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]2[C:15](=[O:16])[CH2:14][CH:12]([C:11]([OH:19])=[O:18])[CH2:13]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CC(C)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(N2CC(C(=O)O)CC2=O)cc1
Temperature: 125 °C
Reaction time: 0.33 h
Yield: 751.6 %

Procedure:
A mixture of 4-isopropylaniline (0.76 g, 0.565 mmol) and itaconic acid (0.70 g, 0.538 mmol) was heated at 120-130° C. in a sealed tube for 2.5 hrs. The mixture was cooled and dissolved in 10% NaOH solution (15 ml) and stirred for 20 min. The aqueous layer was washed with ethyl acetate and acidified with dil. HCl. The precipitate was filtered to obtain 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid (1.0 g, 75%).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1.CC([O-])(C)C.[Na+]>CN(C=O)C.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>[CH2:25]([N:24]([CH2:27][CH3:28])[CH2:23][CH2:22][NH:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:37]3[CH:38]=[N:39][NH:40][CH:41]=3)=[CH:3][N:4]=2)=[CH:13][CH:14]=1)(=[O:20])=[O:19])[CH3:26]
Reactant: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)cc1

Procedure:
In the same way as described for Compound 85, step 1, using 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino)-N-(2-diethylaminoethyl)benzenesulfonamide (100 mg, 0.21 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (17 mg, 0.086 mmol), Pd(PPh3)4 (9 mg, 0.007 mmol) and NaOtBu (27 mg, 0.29 mmol) in DMF:water (3:1, 6 mL). The crude residue is chromatographed on silica gel, eluting with DCM followed by 97:3 DCM:NH3 (7M in MeOH). The fractions containing the desired product are combined and evaporated, to afford the title compound as a yellow solid. HPLC (254 nm): Rt 2.04 min (97.2%); m/z (APCI) 455 (M+H)+
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([F:17])[CH:3]=1.[Cu](C#N)[C:19]#[N:20].C(N)CN>CN(C=O)C>[C:19]([C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([F:17])[CH:3]=1)#[N:20]
Reactant: O=C(NC1CCCCC1)c1ccc(Br)cc1F
Reactant: N#C[Cu]C#N
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)NC2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Heat a mixture of 4-bromo-N-cyclohexyl-2-fluoro-benzamide (1.24 g, 4.13 mmol) and copper cyanide (740 mg, 8.26 mmol) in DMF (20 mL) to reflux for 16 h. Cool the mixture to ambient temperature, add aqueous ethylenediamine and stir for 30 min. Extract the mixture with hexane/EtOAc (1:1), dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (5:1) to give the desired intermediate as a white solid (620 mg, 61%). MS (ES−) m/z: 245 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.Br[CH2:29][C:30]([NH2:32])=[O:31].CCN(C(C)C)C(C)C>>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:2]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: NC(=O)CBr
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCN(CC(N)=O)C1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), 2-bromo-acetamide (57 mg, 0.414 mmol) and DIPEA (215 mL, 1.24 mmol) in IMS (2 mL) was stirred in a sealed vial at 70° C. for 20 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM). The product containing fractions were concentrated in vacuo and the resulting residue was triturated with MeOH affording 133 (59 mg, 34%). LCMS: RT 1.80 min [M+H]+ 420.1. 1H NMR (DMSO, 400 MHz): δ 8.25 (1H, s), 8.14 (1H, s), 8.01-7.90 (1H, m), 7.74-7.66 (1H, m), 7.63-7.55 (1H, m), 7.28-7.03 (4H, m), 5.95 (1H, bs), 4.75 (1H, br), 3.04-2.86 (4H, m), 2.74 (1H, bd, J=11.16 Hz), 2.24 (1H, bt, J=11.70 Hz), 1.80-1.55 (5H, m), 1.35-1.19 (1H, m)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.351 g, 77%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.595 g, 1.324 mmol) and methylamine (1.86 g, 60.0 mmol). 190-192 mp ° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH2:38][C:39]([F:42])([F:41])[F:40])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.Cl.C(OCC)C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[N:21]1([CH2:20][CH2:19][O:18][C:17]2[CH:27]=[CH:28][C:14]([O:13][C:9]3[C:8]([C:29]4[CH:34]=[CH:33][C:32]([S:35]([CH2:38][C:39]([F:40])([F:41])[F:42])(=[O:36])=[O:37])=[CH:31][CH:30]=4)=[CH:7][CH:6]=[C:5]4[C:10]=3[CH:11]=[CH:12][C:3]([OH:2])=[CH:4]4)=[CH:15][CH:16]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)CC(F)(F)F)cc3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(CC(F)(F)F)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 0 °C
Yield: 63.5 %

Procedure:
Dissolve the compound of Example 37 (26 mg, 0.043 mmol) in dichloromethane (1 mL) and add 2M HCl in diethyl ether (43 μL, 0.086 mmol). Remove the solvents in vacuo and place on a high vacuum pump for 10 minutes. Dissolve the resultant foam in dry dichloromethane (1 mL) and cool to 0° C. Add BBr3 (20 μL, 0.22 mmol) dropwise and stir at 0° C. for 1 hour. Pour the reaction into cold saturated aqueous sodium bicarbonate (5 mL) and extract with dichloromethane (2×5 mL). Dry the combined organic phases with sodium sulfate, filter, and concentrate in vacuo. Purify the resultant oil on a SiO2 column with methanol in dichloromethane (0 to 8%) to yield 16 mg of the title compound (64%): mass spectrum (ion spray) m/z=586.4 (M+H).