Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C1C=CC2N(O)N=NC=2C=1.C(NC(C)C)(C)C.C(Cl)CCl.[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37]2[C:40]([NH:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([C:53](O)=[O:54])=[C:49]([F:56])[CH:48]=3)=[C:41]([Cl:44])[CH:42]=[CH:43][C:36]=2[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37]2[C:40]([NH:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([C:53](=[O:54])[NH:4][CH2:1][CH2:2][CH3:3])=[C:49]([F:56])[CH:48]=3)=[C:41]([Cl:44])[CH:42]=[CH:43][C:36]=2[CH2:35][CH2:34]1)=[O:32])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCCN
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3ccc(C(=O)O)c(F)c3)c2CC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: ClCCCl
Product: CCCNC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Add a solution of n-propylamine (6.3 mg, 0.11 mmol) in anhydrous THF (0.5 mL), HOBT (14.5 mg, 0.11 mmol), a solution of diisopropylamine (27.7 mg, 0.21 mmol) in anhydrous THF (0.5 mL) and EDC (20.5 mg, 0.11 mmol) to a mixture of 3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (48.1 mg, 0.11 mmol) in anhydrous THF (1.4 mL) at room temperature. Stir overnight at room temperature and partition the mixture between EtOAc (50 mL) and saturated aqueous NaHCO3 (20 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (12 g RediSep® column) eluting with hexane/EtOAc (19:1 to 1:1 gradient over 30 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a thick colorless oil (37.1 mg, 71%). MS (ES+) m/z: 490.2 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.C1(C#C)C=CC=CC=1>>[CH2:1]1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3
Reactant: C1=CC2C3C=CC(C3)C2C1
Solvent: C#Cc1ccccc1
Product: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reaction time: 3 h

Procedure:
A 10.0 gram (75.6 mmol) amount of dicyclopentadiene was added to a 20 ml scintillation vial. A 5.0 milligram (7.2 μmol) amount of RuClH(H2)(PCy3)2 was added. One equivalent of phenylacetylene per equivalent of RuClH(H2)(PCy3)2 was added via the addition of 0.1 mls of a 72 mM solution of phenylacetylene. The ring opening polymerization of dicyclopentadiene was observed slowly by a gradual thickening of the solution to a rubbery viscous material after three hours. After 24 hours, the material was soft and rubbery.
Reaction SMILES: [N:1]([CH2:24][C:25]([O:27]N1C(=O)CCC1=O)=O)([CH2:13][C:14]([O:16]N1C(=O)CCC1=O)=O)[CH2:2][C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][S:48]([C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH:57]2[C:66]3[C:61](=[C:62]([Cl:68])[CH:63]=[C:64]([Cl:67])[CH:65]=3)[CH2:60][N:59]([CH3:69])[CH2:58]2)[CH:52]=1)(=[O:50])=[O:49]>>[N:1]([CH2:2][C:3]([NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][S:48]([C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH:57]2[C:66]3[C:61](=[C:62]([Cl:68])[CH:63]=[C:64]([Cl:67])[CH:65]=3)[CH2:60][N:59]([CH3:69])[CH2:58]2)[CH:52]=1)(=[O:50])=[O:49])=[O:5])([CH2:13][C:14]([NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][S:48]([C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH:57]2[C:66]3[C:61](=[C:62]([Cl:68])[CH:63]=[C:64]([Cl:67])[CH:65]=3)[CH2:60][N:59]([CH3:69])[CH2:58]2)[CH:52]=1)(=[O:50])=[O:49])=[O:16])[CH2:24][C:25]([NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][S:48]([C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH:57]2[C:66]3[C:61](=[C:62]([Cl:68])[CH:63]=[C:64]([Cl:67])[CH:65]=3)[CH2:60][N:59]([CH3:69])[CH2:58]2)[CH:52]=1)(=[O:50])=[O:49])=[O:27]
Reactant: O=C(CN(CC(=O)ON1C(=O)CCC1=O)CC(=O)ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)CN(CC(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)CC(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Yield: 11.6 %

Procedure:
Compound 213 was prepared following the procedure outlined in Example 168 using tris(2,5-dioxopyrrolidin-1-yl) 2,2′,2″-nitrilotriacetate (75 mg, 0.156 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 254 mg, 0.467 mmol). Purification by preparative HPLC gave the title compound (32.0 mg) as the TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.88 (d, 3H), 7.75 (s, 3H), 7.63 (t, 3H), 7.54 (t, 6H), 6.82 (s, 3H), 4.84-4.75 (m, 6H), 4.48 (d, 3H), 3.86 (m, 3H), 3.85-3.37 (m, 54H), 3.14 (s, 9H), 3.02 (t, 6H). MS (m/z): 1777.07 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:53][O:54][C:55](=[O:64])[C@@H:56]1[CH2:60][C@H:59]([N:61]=[N+:62]=[N-:63])[CH2:58][NH:57]1>CN(C=O)C.O.C(OCC)(=O)C>[CH3:53][O:54][C:55](=[O:64])[C@@H:56]1[CH2:60][CH:59]([N:61]=[N+:62]=[N-:63])[CH2:58][N:57]1[C:18](=[O:20])[CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CC(N=[N+]=[N-])CN1C(=O)CCc1ccc(CNC(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
2.70 g (9.5 mmol) of 3-(4-tert-butyloxycarbonylaminomethylphenyl)propionic acid (starting compound A6) are dissolved in 40 ml of DMF, and 2.7 ml of triethylamine are added. After stirring for 5 min., 3.63 g of HBTU are added and, after a further 5 min., 2 g of (2S,4S)-4-azidoproline methyl ester hydrochloride. Stirring at RT overnight is followed by addition of ethyl acetate and water and separation of the phases. The organic phase is washed once each with 1N sodium hydroxide solution, 1N hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine. Drying over magnesium sulfate is followed by concentration and drying under high vacuum. 4.1 g of the title compound are obtained as a pale orange oil. The mass spectrum shows the molecular peak MNH4+ at 449 Da.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[S:26]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=2)[N:6]=1)(=[O:28])=[O:27]
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3c(C)cc(Cl)cc3Cl)n2)cc1

Procedure:
The title compound was prepared N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]acetamide and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (8.1 mg) with purity >80%. MS (pos) m/z 456.2, 458.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[C:15]([NH:23][C:24]([NH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOCC
Product: COc1cc(NC(=S)NC(=O)c2ccccc2)c(C(N)=O)cc1OC
Reaction time: 24 h
Yield: 96.3 %

Procedure:
To a stirred mixture of 4 g of 2-amino-4,5-dimethoxybenzamide and 200 ml of ether was added dropwise, e solution of 3.3 g of benzoyl isothiocyanate in 100 ml of ether over 15 minutes. After 24 hours, the solid was collected, giving 7 g of the desired product as white crystals, mp 204°-207° C. (dec.).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[C:16]([NH:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.CN(C)C=O>[C:16]([NH:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[CH:27]=2)[CH2:22]1)(=[O:18])[CH3:17]
Reactant: COC(=O)CCC(=O)O
Reactant: CC(=O)NCC1Cc2ccccc2C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(CNC(C)=O)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To 48.3 g of methyl hydrogen succinate dissolved in 840 ml of dichloroethane were added 46.4 g of oxalyl chloride and 2 drops of dimethylformamide. The mixture was stirred at room temperature for 5 hours. Then, under ice cooling, 34.6 g of 2-(acetylaminomethyl)indane dissolved in 280 ml of dichloroethane and 97.6 g of anhydrous aluminum chloride were added to the reaction mixture. After the mixture was stirred for 1 hour, the reaction mixture was poured into ice water. The organic layer was collected by separation, washed with water and dried, and the solvent was removed to obtain 51.8 g of 2-(acetylamino)methyl-5-(3-methoxycarbonylpropionyl)indane.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:33](O)(=[O:37])[CH2:34][CH2:35][CH3:36].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:33]([N:16]([CH2:15][C:13]1[CH:12]=[CH:11][C:3]([O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]([CH3:1])[CH:14]=1)[C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC(=O)O
Reactant: CCOC(=O)COc1ccc(CNc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.7 %

Procedure:
To a solution of ethyl [2-methyl-4-({[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)phenoxy]acetate (0.07 g, 0.16 mmol) in anhydrous CH2Cl2 (2 mL) at 0° C. under nitrogen was added butyric acid (0.016 mL, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (33 mg, 0.17 mmol) was then added in portions followed by triethylamine (0.022 mL, 0.16 mmol). After stirring for 15 mins at 0° C. the reaction was allowed to attain room temperature and stirred for 18 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and shaken with 1 M HCl (5 mL). The organic extract was separated by hydrophobic frit and the solvent removed in vacuo. Purification by Biotage™ chromatography (Silica, 12 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (40 mg).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50](Br)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=1)#[N:55].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50]([C:60]3[CH:59]=[CH:58][CH:57]=[C:56]([C:54]#[N:55])[CH:61]=3)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#Cc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)s2)c1

Procedure:
A mixed solution of 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 53 (1.24 g) obtained in Example 119-(6), 3-cyanophenylboronic acid (270 ml), bis(triphenylphosphine)palladium (II)dichloride (54 mg) and 2M aqueous sodium carbonate solution (2.3 ml) in 1,2-dimethoxyethane (12 ml) was heated under reflux for 4 hours. The mixture was diluted with ethyl acetate and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1-5:1) to give 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene (1.12 g) as colorless oil. APCI-Mass m/Z 849/851 (M+NH4).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[CH2:26][N:25]([C:27](=[O:44])[CH2:28][N:29]([CH2:37][CH2:38][C:39]3[NH:43][N:42]=[N:41][CH:40]=3)C(=O)OC(C)(C)C)[CH2:24][C:22]=2[N:23]=1>ClCCl>[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[CH2:26][N:25]([C:27](=[O:44])[CH2:28][NH:29][CH2:37][CH2:38][C:39]3[NH:43][N:42]=[N:41][CH:40]=3)[CH2:24][C:22]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)N(CCc1cnn[nH]1)CC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNCCc1cnn[nH]1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Add trifluoroacetic acid (3 mL) slowly to a 0° C. solution containing tert-butyl {2-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-2-oxoethyl}[2-(1H-1,2,3-triazol-5-yl)ethyl]carbamate (0.15 g; 1.0 equiv; 0.297 mmoles) in dichloromethane (1 mL). Stir for 2 hours, then warm to ambient temperature and stir for 30 minutes. Concentrate the mixture and dissolve the residue in dichloromethane (20 mL). Add saturated sodium bicarbonate (20 mL), brine (20 mL), and water (50 mL), and extract with dichloromethane (6×20 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-2-{[2-(1H-1,2,3-triazol-5-yl)-ethyl]amino}ethanone (0.093 g; 77%) as a yellowish foam: MS (m/z): 405(M+1).
Reaction SMILES: CCCCCC.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[OH:15])=[CH:10][CH:9]=1.Br[CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34].CCOCC>CS(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:15][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:12][CH:13]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)=CCBr
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)=CCOC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
Dry DMSO (20 mL) was added to 14 mmol of hexane-washed KH under Ar with stirring at RT. After H2 evolution ceased, a solution of tris-(p-chlorophenyl) methanol (3.63 g, 10 mmol) in 25 mL dry DMSO was added, giving a deep red anion solution. After 5 min, 1-bromo-3-methyl-2-butene (2.0 mL, 19 mmol) was added and stirring continued for 1 h. The crude product was isolated by Et2O extraction and purified by flash chromatography (75 g SiO2, 5% EtOAc-hexanes) giving 3.93 g (91%) of (3-methyl-2-butenyl) tris-(4-chlorophenyl)methyl ether as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([O:11]C)=[O:10])[CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COC(=O)Cc1cc(Br)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(Br)cc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
To a mixture of methyl 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.80 g), tetrahydrofuran (3 mL) and methanol-(3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1.5 hrs. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (0.63 g, 83%) of 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 162-163° C.
Reaction SMILES: [N:1]1[NH:2][C:3]([NH:6][C:7]([C:9]2[C:14]([NH2:15])=[N:13][C:12]([C:16]([F:19])([F:18])[F:17])=[C:11](Br)[N:10]=2)=[O:8])=[CH:4][CH:5]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:1]1[NH:2][C:3]([NH:6][C:7]([C:9]2[C:14]([NH2:15])=[N:13][C:12]([C:16]([F:19])([F:18])[F:17])=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:10]=2)=[O:8])=[CH:4][CH:5]=1
Reactant: C1COCCN1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1ccn[nH]1
Product: Nc1nc(C(F)(F)F)c(N2CCOCC2)nc1C(=O)Nc1ccn[nH]1

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2H-pyrazol-3-yl)-amide (Ex. 6) (42 mg, 0.120 mmol) and morpholine (1 ml, 11.3 mmol) was heated at 100-140° C. using microwave for 8 hours and 15 minutes. The reaction mixture was concentrated in vacuo and purification of the residue by preparative LC-MS afforded the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10](=[O:18])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:15]=2)[C:10](=[O:18])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=C1NC(Cc2ccccc2)c2cc(O)ccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(Cc1ccccc1)NC2=O
Temperature: 80 °C
Yield: 73.5 %

Procedure:
A mixture of 3-benzyl-5-hydroxyisoindolin-1-one (360 mg, 1.51 mmol), CsCO3 (980 mg, 3.01 mmol) and tert-butyl 2-bromoethylcarbamate (506 mg, 2.26 mmol) in 4 mL of acetonitrile was heated up to 80° C. for 4 hours, TLC showed complete conversion. The solvent was evaporated and the residue was dissolved in ethyl acetate, then water was added, this was separated. The organic phase was dried on Na2SO4 and the solvent was evaporated. The residue was purified by flash-chromatography on silica gel with 100% ethyl acetate, 426 mg (1.11 mmol, 74%) of the product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38]C)[CH:33]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(O)c4)nc4sccn34)n2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-methoxy-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (6.98 g, 12.03 mmol) in methylene chloride (100 ml) is cooled to −78° C. and slowly treated with 1 molar solution of boron tribromide in methylene chloride (65 ml). The reaction mixture is kept at −78° C. for one hour then is allowed to warm to room temperature for two hours. The mixture is quenched by the addition of methanol (25 ml) at 0° C. and is stirred at room temperature for an additional hour. The mixture is diluted with methylene chloride (500 ml) and washed with three portions of 100 ml of saturated sodium bicarbonate solution, two portions of 100 ml of water and two portions of 100 ml of saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated in vacuo, giving a yellow foam. The crude product is recrystallized from methanol as a yellow solid (4.85 g, 71%). M.p.=174-177° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 9.4 (br. s, 1H), 8.70 (br. s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.8-7.7 (m, 2H), 7.7-7.65 (m, 2H), 7.40 (d, J=4.7 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.15 (d, J=7.4 Hz, 1H), 7.0-6.95 (m, 1H), 6.85-6.8 (m, 1H), 6.44 (d, J=5.5 Hz, 1H), 3.95 (br. s, 1H), 3.72 (dd, J=10.6 3.1 Hz, 1H), 3.40 (m, 1H), 2.5-2.4 (m, 1H), 2.35 (t, J=10.2 Hz, 1H), 2.0-1.8 (m, 2H), 1.65-1.5 (m, 1H), 1.46-1.32 (m, 1H). LCMS: 567 [M+H]. Calc. for C26H23N6O3S2Cl 0.5 water 1.0 methanol: C, 53.33; H, 4.64; N, 13.82; found. C, 53.32; H, 4.64; N, 13.82.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:12]([C:9]1[O:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:8]=1)=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)NCc3ccccc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and benzylamine to give N-benzyl-7-methoxybenzofuran-2-carboxamide (Compound 269a). Successively, it was formylated to give N-benzyl-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 269b), then compound 269b was reacted with methylamine hydrochloride to give compound 269 as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([CH2:10][C:11]([OH:13])=[O:12])=[C:5]([F:14])[CH:4]=1)#[N:2].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[C:8]([F:9])[C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:14]
Reactant: N#Cc1cc(F)c(CC(=O)O)cc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(F)c(C#N)cc1F
Temperature: 85 °C

Procedure:
(4-Cyano-2,5-difluorophenyl)acetic acid (0.5 g, 2.5 mmol) was dissolved in methanol (20 mL), and thionyl chloride (0.5 mL) was added drop wise to the solution. The reaction was heated to 85° C. for 4 hours. Then it was cooled and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and the filtrate was evaporated to dryness under reduced pressure to yield the title compound after purification on silica gel (eluted with 5-20% ethyl acetate-hexanes) as an off white solid. 1H NMR (500 MHz, CDCl3): δ 7.31 (dd, J=5.2, J=5.2 Hz, 1H), 7.19 (dd, J=5.7, J=5.8 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 2H). LC-MS (IE, m/z): 212 [M+1]+.