Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCCc1ccccn1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCc3ccccn3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-(2-aminoethyl)pyridine (0.012 mL, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(2-(pyridin-2-yl)ethyl)aminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-c2ccccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyridinyl)-benzaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[C:27]([NH:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:29])[CH3:28]>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=[C:2]([C:35]3[CH:36]=[C:31]([NH:30][C:27](=[O:29])[CH3:28])[CH:32]=[CH:33][CH:34]=3)[C:3]=2[CH:17]=[CH:16][C:15]1=[O:18]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(F)cc1F
Product: CC(=O)Nc1cccc(-c2nc(NC(CO)CO)nc3c2ccc(=O)n3-c2ccc(F)cc2F)c1

Procedure:
The title compound was prepared by following the procedure in example 96d from 4-chloro-8-(2,4-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one and [3-(acetylamino)phenyl]boronic acid: LC-MS m/z 482 (M+H)+, retention 2.69 min.
Reaction SMILES: [CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1.[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH:13][C:16](=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1
Reactant: Nc1ccc2oc3c(c2c1)CCC3
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc2oc3c(c2c1)CCC3
Yield: 62.2 %

Procedure:
Following the procedure of Example 1, 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (0.69 g, 4.0 mmol) and trimethylacetyl chloride (0.55 mL, 4.4 mmol) in pyridine (10 mL) provided N-(2,3-dihydro-1H-cyclopenta(b)benzofuran-7-yl)-2,2-dimethyl-propionamide (0.64 g). Mp 188.5-190.0° C.; MS m/z 258 ([M+H]+); Anal. Calcd. for C16H19NO2: C, 74.68; H, 7.44; N, 5.44; Found: C, 74.67; H, 7.43; N, 5.39.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)[CH3:20]>N1C=CC=CC=1>[CH2:1]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([O:18][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=3)=[O:17])[CH:12]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOc1ccc(O)cc1
Reactant: CCCCCC1CCc2cc(C(=O)O)ccc2C1
Solvent: c1ccncc1
Product: CCCCCC1CCc2cc(C(=O)Oc3ccc(OCC)cc3)ccc2C1
Yield: 97.3 %

Procedure:
Analogously to Example 1, 6.16 g of 2-pentyl-1,2,3,4-tetrahydronaphthalene-6-carboxylic acid are converted into the acid chloride and this is reacted with 3.45 g of p-ethoxyphenol in 15 ml of absolute pyridine. There are obtained 8.9 g of crude p-ethoxyphenyl 2-pentyl-1,2,3,4-tetrahydro-6-naphthoate which, for purification, is chromatographed on 230 g of silica gel. Elution with toluene/hexane (1:1) and toluene/hexane (7:3) yields 8.8 g of substance which are recrystallized from acetone/hexane up to constant melting point and clearing point and dried in a high vacuum (0.01 mbar). There are obtained colorless crystals of p-ethoxy-phenyl 2-pentyl-1,2,3,4-tetrahydro-6-naphthalene; m.p. 95.4°-96.2° C., cl.p. 119.0°-119.4° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]([OH:16])=O)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[CH2:42][NH2:43].Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[CH2:42][NH:43][C:14](=[O:16])[C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Reactant: NCc1ccc(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1Cl)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
5-Oxo-1-(phenylmethyl)-proline (0.176 g, 0.80 mmol, prepared as described below) was dissolved in dichloromethane (3 ml) and to this was added 1-hydroxybenzotriazole (0.119 g, 0.88 mmol), triethylamine (0.113 ml, 0.81 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.134 g, 0.84 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.169 g, 0.88 mmol) under an atmosphere of argon. The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was filtered through a phase separator and then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-5-oxo-1-(phenylmethyl)-prolinamide (0.112 g) as a white solid.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([OH:20])=[C:14]([C:16](OC)=[O:17])[N:15]=1>C1COCC1>[CH3:1][NH:2][C:16]([C:14]1[N:15]=[C:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([CH3:22])[C:12](=[O:21])[C:13]=1[OH:20])=[O:17]
Reactant: CN
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)n(C)c(=O)c1O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(Cc2ccccc2-c2ccccc2)n(C)c(=O)c1O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 40.2 %

Procedure:
A sealed tube containing 2M solution of methylamine (1.71 ml, 3.42 mmol) in THF and methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.1 g, 285 μmol) was heated at 100° C. in a microwave oven for 20 min, cooled and filtered. The solid was stirred in MeOH, in the presence of Amberlyst 15 IE resin, at 60° C. for 5 min and then at room temperature for 1 h, filtered, evaporated to dryness and triturated with Et2O to give the title compound as a white solid (0.040 g; 40%). LCMS: m/z=351 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[NH:30]1[CH2:35][CH2:34][S:33][CH2:32][CH2:31]1>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:30]2[CH2:35][CH2:34][S:33][CH2:32][CH2:31]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1CSCCN1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example A1) (2.9 g, 8.94 mmol), Et3N (5.6 mL, 40.23 mmol) and thiomorpholine (2.6 mL, 26.82 mmol) was stirred in DMSO (36 mL) at 23° C. according to the general procedure B. Obtained as a yellow solid (3.6 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].[Cu][C:14]#[N:15]>CN1CCCC1=O>[C:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12])#[N:15]
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2nc[nH]c(=O)c2c1
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
6-Iodoquinazolin-4-one (10 g) in 1-methyl-2-pyrrolidinone (50 ml) was treated with copper (I) cyanide (4.28 g) at 206° C. under N2 for 16 hours. The resulting mixture was cooled to 170° C. and the methyl-2-pyrrolidinone removed by vacuum distillation. Potassium cyanide (2.4 g) in water (30 ml) and ethyl acetate (150 ml) were added to the cooled residue and heating continued at 110° C. for 1.5 hours. This mixture was then filtered hot through a pad of celite and the filter cake washed thoroughly with ethyl acetate. Subsequent separation, drying and concentration in vacuo gave the title compound (2.29 g) as a beige solid; δH [2H6]DMSO 12.65(1H, bs), 8.53(1H, d), 8.28(1H, s), 8.19(1H, dd), 7.82(1H, d); m/z (M−1+) 171.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:1][C@H:2]2[CH2:3][C@@H:4]([NH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH2:5]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=C(N[C@H]1C[C@@H](O)C1)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](NC(=O)OCc3ccccc3)C2)cc1

Procedure:
A solution of benzyl (cis-3-hydroxycyclobutyl)carbamate (intermediate 47, 0.3 g, 1.356 mmol), p-toluenesulfonyl chloride (0.284 g, 1.492 mmol), and triethylamine (0.567 ml, 4.07 mmol) in dichloromethane (2.71 ml) was stirred at room temperature for 14 hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, rotovapped, and advanced to next step directly.
Reaction SMILES: Cl.[Cl:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([CH2:13][NH2:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:14][CH2:13][C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:12][C:3]([Cl:2])([CH2:10]3)[CH2:4]1)[CH2:6]2)=[O:19]
Reactant: NCC12CC3CC(CC(Cl)(C3)C1)C2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Product: O=C(NCC12CC3CC(CC(Cl)(C3)C1)C2)c1ccccc1Cl

Procedure:
Prepared according to the method of Example 1 from 3-chloro-tricyclo[3.3.1.13,7]decane-1-methanamine, hydrochloride (0.061 g) and 2-chlorobenzoyl chloride (0.0.32 ml) to give the title compound as a white solid (0.093 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[NH:34])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:35]=[C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)=[CH:31][CH:30]=3)[N:34]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)s1

Procedure:
By condensation between 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-[4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine nitrate. Light yellow solid. 1H-NMR (CDCl3), δ: 2.37 (s, 3H, CH3), 2.61 (m, 4H, CH2), 2.69 (s, 3H, CH3), 2.70 (s, 3H, CH3), 3.20 (m, 4H, CH2), 6.88 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.94 (s, 1H, NH), 6.96 (d, 2H, J=8.8 Hz, Ph-H), 7.51 (d, 2H, J=8.8 Hz, Ph-H), 8.38 (d, 1H, J=5.1 Hz, pyrimidinyl-H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:28]2[O:27][CH:31]=[CH:30][CH:29]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccco1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)cc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccco2)cc1

Procedure:
By carrying out the operation analogously to example 3, starting from 4-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 2-furanboronic acid, the expected product is obtained and is reacted further without additional purification in order to obtain the nonacetylated xyloside.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][N:15]([CH3:29])[C:16]([C:18]1[S:19][CH:20]=[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]=12)=[O:17].[I:30]I>C1COCC1>[CH3:13][O:14][N:15]([CH3:29])[C:16]([C:18]1[S:19][C:20]([I:30])=[C:21]2[CH2:26][C:25]([CH3:27])([CH3:28])[CH2:24][CH2:23][C:22]=12)=[O:17]
Reactant: II
Reactant: CON(C)C(=O)c1scc2c1CCC(C)(C)C2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1sc(I)c2c1CCC(C)(C)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution of diisopropylamine (11.02 g, 109 mmol) in THF (400 mL) is added n-butyl lithium (72.7 mL, 109 mmol, 1.5 M in pentane) at 0-5° C. The solution is cooled to −78° C. and a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (23 g, 91 mmol) in THF (100 mL) is added. Upon complete addition, the mixture is stirred for 20 min at −78° C. before a solution of iodine (30 g, 119 mmol) in THF (100 mL) is added. Stirring is continued at −78° C. for 30 min. The reaction is quenched by slowly adding a 1:1 mixture of water/methanol (20 mL). The solution is diluted with water (400 mL) and extracted with diethyl ether (3×100 mL). The combined organic extracts are washed with 10% aq. citric acid solution and brine, dried over Na2SO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with DCM to afford 3-iodo-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (18 g) as a brownish oil; LC-MS: tR=1.09 min, [M+1]=380.21.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:11]=[C:10]([C:12]3[CH:26]=[CH:25][C:15]([CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:14][CH:13]=3)[CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:4][NH:5][C:6]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:25][CH:26]=3)[CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccnc(NCC3CC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(-c2ccnc(NCC3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Dissolve 4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-N-(tert-butoxycarbonyl)-benzylamine (195 mg, 0.55 mmol) in DCM (3 mL) and add trifluoroacetic acid (1.5 mL). Stir at room temperature for 3 h. Concentrate in vacuo and purify the crude mixture by SCX chromatography (5 g) to obtain the title compound (140 mg, 93%) suitable for use without additional purification. MS (ES+) m/z: 255 (M+H)+.
Reaction SMILES: [CH3:1][Mg]I.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH:24]=3)[C:19]([C:34](=[O:36])[CH3:35])=[CH:18]2)=[N:15][CH:16]=1>C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[N:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:27])[CH:24]=3)[C:19]([C:34]([OH:36])([CH3:1])[CH3:35])=[CH:18]2)=[N:13][CH:12]=1
Reactant: CC(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(C)(O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: -30 °C
Reaction time: 2 h

Procedure:
Methyl magnesium iodide (3M solution in diethyl ether, 0.14 mL, 0.439 mmol, 1.5 eq) was added at −50° C. to a stirred solution of 184a) (130 mg, 0.292 mmol, 1.0 eq) in dry THF (10 mL). The reaction mixture was stirred for 2 h at −30° C., then quenched with ammonium chloride solution, diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The remnant was purified by preparative TLC using ethyl acetate/pet ether (7:3) as eluent. White solid. Yield: 50 mg (37% of theory).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:7]3[CH:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:9][N:8]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(C)(O)c1cc(C(=O)O)no1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)on1
Yield: 36 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylic acid (0.096 g, 0.560 mmol) of Example 77(a) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.12 g, 0.431 mmol) of Example 116(f). The product was purified by recrystallization from ethanol. Yield 36.0%. 1H-NMR (400 MHz; DMSO-d6): 1.16 (d, 3H), 1.47 (s, 6H), 4.32 (d, 2H), 4.39-4.51 (m, 1H), 5.67 (s, 1H), 6.49 (s, 1H), 7.01 (d, 1H), 7.85 (d, 1H), 7.87 (dd, 1H), 7.99 (s, 1H), 8.74 (d, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([OH:19])=O.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:27][CH:28]=1)=[O:19]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CC#N
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Carbonyldiimidazole (2.367 g, 14.60 mmol) was added to a stirred solution of 2-bromoisonicotinic acid (2.4572 g, 12.16 mmol) in MeCN (30 mL) and the RM was stirred at RT for 3 h. 4-(trifluoromethoxy)aniline (2.467 mL, 18.25 mmol) was added and RM was stirred at RT overnight. and the mixture was treated with sat. aq. Na2CO3 (50 mL) and extracted with TBME. The combined extracts were washed with aq. HCl (pH=3), brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to a residue which was triturated with n-heptane and filtered to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=1.55 min, m/z=360.9-362.9 [M+H]+, m/z=358.9-360.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.40 (d, J=8.56 Hz, 2H) 7.77-7.97 (m, 3H) 8.12 (s, 1H) 8.61 (d, J=5.14 Hz, 1H) 10.72 (s, 1H).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:16]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.[NH2:32][C:33]1[CH:34]=[C:35]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:36]([Cl:39])=[N:37][CH:38]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:39][C:36]1[C:35]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:34][C:33]([NH:32][C:2]2[C:3]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:4][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:9])=[CH:6][N:7]=2)=[CH:38][N:37]=1
Reactant: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)c2ncn(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine (0.157 g, 0.368 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330 step 2, 0.103 g, 0.462 mmol) in THF (2 mL) in 20 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 1.47 mL, 1.47 mmol) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 30 min. The mixture was partitioned between a mixture of saturated aqueous sodium chloride (10 mL)/buffer (pH 5.0, citric acid/NaOH) (10 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50 g, eluent: iPrOH in CHCl3 0% to 10%) to afford N-(2-chloro-5-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(1-morpholinoethyl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide (0.169 g, 73% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 13.18 (s, 1H) 9.78 (d, J=1.96 Hz, 1H) 8.83 (d, J=2.54 Hz, 1H) 8.63 (d, J=2.54 Hz, 1H) 8.36 (d, J=2.35 Hz, 1H) 8.31 (s, 1H) 6.76 (br. s., 1H) 5.85-5.90 (m, 1H) 4.17-4.24 (m, 1H) 3.79-3.88 (m, 1H) 3.73 (t, J=4.50 Hz, 4H) 3.51-3.59 (m, 1H) 3.14 (s, 3H) 2.94 (s, 3H) 2.45-2.62 (m, 4H) 2.01-2.22 (m, 3H) 1.66-1.93 (m, 3H) 1.48 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion): 628.0 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:14]1)=[O:11])=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of (R)-3-(N-(tert-butoxycarbonyl)glycyl)amino-1-(4-chlorobenzyl)pyrrolidine (5.39 g, 14.7 mmol) in methanol (60 mL) was added 4 N HCl in dioxane (38 mL). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and 2 N NaOH solution (80 mL) was added. The mixture was extracted with dichloromethane (80 mL×3), and the combined extracts were dried over sodium sulfate and concentrated. Column chromatography (SiO2, AcOEt/EtOH/Et3N=90/5/5) gave (R)-3-(glycyl)amino-1-(4-chlorobenzyl)pyrrolidine (3.374 g, 86%): 1H NMR (CDCl3, 270 MHz) δ1.77 (dd, J=1.3 and 6.9 Hz, 1H), 2.20-3.39 (m, 2H), 2.53 (dd, J=3.3 and 9.6 Hz, 1H), 2.62 (dd, J=6.6 and 9.6 Hz, 1H), 2.78-2.87 (m, 1H), 3.31 (s, 2H), 3.57 (s, 2H), 4.38-4.53 (br, 1H), 7.18-7.32 (m, 4H), 7.39 (br. s, 1H).