Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.Cl.Cl.[CH3:11][NH:12][O:13][CH3:14].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:14][O:13][N:12]([CH3:11])[C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1ccoc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CON(C)C(=O)c1ccoc1

Procedure:
The title compound was prepared from furan-3-carboxylic acid (3.4 g, 0.030 mol), N,O-dimethylhydroxylamine hydrochloride hydrochloride (2.9 g, 0.030 mol) triethylamine (8.3 mL, 0.060 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (13.3 g, 0.030 mol) according to the general procedure described in Example 1 for N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide. NMR (DMSO-d6) δ8.25 (1H, s), 7.75 (1H, s), 3.70 (3H, s), 3.22 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]([C:38](OC)=[O:39])([CH3:37])[CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]([CH3:37])([CH3:36])[CH2:38][OH:39])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Br)ccc2OCC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Yield: 11.3 %

Procedure:
In a manner similar to the method described in Example 231, racemic (2′S,3S,4′R)-4′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.187 mmol) was reacted with LiAlH4 (35 mg, 0.934 mmol) in THF and the crude product was purified by Prep-HPLC to give title compound as a white solid (13 mg).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=4)[N:8]=3)[CH:6]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.68) (0.73 g, 1.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.46 g, 1.8 mmol) according to the general procedure VI. Obtained as a light brown solid (0.128 g), which was subsequently deprotected.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][CH:13]=1)=[O:6])C>CO>[CH3:2][O:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][CH:13]=1)=[O:6]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1c1c[nH]c2ccc(C#N)cc12
Agent: [Na]
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@H]1c1c[nH]c2ccc(C#N)cc12

Procedure:
Sodium metal (13.5 g, 556 mMol) was carefully added portion-wise to anhydrous methanol (400 mL). A solution of cis-2-(5-cyanoindol-3-yl)-cyclopentanecarboxylic acid ethyl ester (33.1 g, 117 mMol) in methanol (100 mL) was added over 5 minutes. The mixture was heated at a gentle reflux for 18 hours, carefully quenched with water, and evaporated in vacuo. The residue was dissolved ethyl acetate (600 mL), washed with saturated sodium chloride (100 mL), dried over sodium sulfate, and concentrated in vacuo to give the product as an 88:12 cis/trans diastereomeric mixture which was used without further purification (27 g, 86%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:39])C>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=3[O-:39])[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Solvent: CC(=O)O
Product: COc1ccccc1Oc1c(Cl)nc(-c2cccc[n+]2[O-])nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
A suspension of 525 mg of 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidin-4-yl]benzenesulfonamide in 1 ml of glacial acetic acid was treated with 2.5 ml of 40% peracetic acid and slowly heated to reflux. After 2 minutes the mixture was cooled, evaporated under reduced pressure and the residue was recrystallized from ethyl acetate. There was obtained 2-[4-(4-tert-butyl-phenylsulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1-oxide of m.p. 201°-202° C. (with decomposition).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19].C([N-]C(C)C)(C)C.[Li+]>>[CH3:20][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:28])[CH3:29])[C:22]=1[NH:30][C:31](=[O:32])[CH2:10][C:9](=[O:11])[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:19]
Reactant: CC(=O)CC(c1ccccc1)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)CC(c1ccccc1)c1ccccc1

Procedure:
The title compound, mp 146°-148° C., was prepared from 4,4-diphenylbutan-2-one (3.50 g, 0.015 mol), 2.6-diisopropylphenyl isocyanate (3.17 g, 0.015 mol) and lithium diisopropylamide (0.015 mol) using the procedure described in Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[N:3][CH:4]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(NCCc3c[nH]c4ccccc34)ncc2F)c1
Yield: 52.4 %

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and tryptamine (100 mg, 0.62 mmol) gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(indol-3-yl)ethyl]-2,4-pyrimidinediamine (40 mg, 53%). 1H NMR (CD3OD): δ 3.01 (t, J=7.2 Hz, 2H), 3.61 (t, J=7.2 Hz, 2H), 6.51 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.96 (td, J=0.9 and 7.2 Hz, 1H), 7.03-7.09 (m, 3H), 7.22 (d, J=7.5 Hz, 1H), 7.28-7.32 (m, 2H), 7.53 (d, J=7.8 Hz, 1H), 7.72 (d, J=4.5 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ−171.72; LCMS: ret. time: 20.17 min.; 95.66%; MS (m/e): 364.05 (Ma).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]([OH:27])[N:11]([C:18]([CH3:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:12]2=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.[I:47]I>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][C:14]([I:47])=[C:13]2[C:9]=1[CH:10]([OH:27])[N:11]([C:18]([CH3:19])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:26])[C:12]2=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: CC(C)(c1ccccc1)N1C(=O)c2cccc(Oc3ccccc3)c2C1O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2c(I)ccc(Oc3ccccc3)c2C1O
Yield: 74.8 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-phenoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (700 mg, 1.95 mmol) was dissolved in THF (28 mL), and the solution was treated with TMEDA (0.94 mL, 6.2 mmol), sec-butyllithium-hexane solution (1.01 mol/L, 6.20 mL, 6.24 mmol) and iodine (594 mg, 2.34 mmol), followed by purification by flash column chromatography (chloroform/methanol=100/0, 99/1) to obtain 4-phenoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (708 mg, yield 75%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=1[S:35][CH3:36])[C:11]1[C:12](=[O:27])[CH2:13][CH2:14][C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C(#N)C>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([CH:10]2[NH:9][C:37](=[O:38])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[C:15]3[CH2:14][CH2:13][C:12](=[O:27])[C:11]2=3)=[C:29]([S:35][CH3:36])[CH:30]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSc1cc(Br)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (250 μL, 1.81 mmol) is added to a mixture of 2-(amino(4-bromo-2-(methyl-thio)phenyl)methyl)-3-(3-(trifluoromethyl)phenyl amino)cyclopent-2-enone hydrochloride (intermediate 20.5, 4.08 g, 7.23 mmol based on 90% purity) and 1,1′-carbonyldiimidazole (1.46 g, 9.04 mmol) in acetonitrile (54 mL), and the mixture is stirred at room temperature for 1 h. All volatiles are removed under reduced pressure, and the residue is treated with water. The precipitate is filtered and purified by flash chromatography on silica (gradient dichloromethane to dichloromethane/methanol 95:5). Yield: 3.04 g; ESI mass spectrum: [(79Br)-M+H]+=497, [(81Br)-M+H]+=499; Retention time HPLC: 0.65 min (X011_S03).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1CCC[CH2:21]1.C([Li])CCC.CN(C)C=O>O>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:21]=[O:20])[C:12]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (613, 3.83 g, 14.5 mmol) in tetrahydrofuran (148 mL, 1.82 mol). The solution was chilled to −78° C. and n-butyllithium (1.60 M in hexane, 19.1 mL, 30.0 mmol) was added over 30 minutes followed by the addition of, N,N-dimethylformamide (1.12 mL, 14.5 mol). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and crystallized from ether to give compound 614 (3.0 g, 71%).
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8].[Cl:28]N1C(=O)CCC1=O.BrN1C(=O)CCC1=O>>[Cl:28][C:2]1[C:3]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8]
Reactant: Nc1c(Br)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C1CCC(=O)N1Br
Product: Nc1c(Cl)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
6-Chloro-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine was synthesized in a manner similar to the synthesis of 6-bromo-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine, but with N-chlorosuccinimide substituted for N-bromosuccinimide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[NH:10][S:9]1(=[O:19])=[O:18].[Br:20][CH2:21][CH2:22][CH2:23]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Na+]>O1CCCC1>[Br:20][CH2:21][CH2:22][CH2:23][N:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:19])=[O:18]
Reactant: OCCCBr
Reactant: O=S1(=O)Nc2ccccc2CN1c1ccccc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)N(c2ccccc2F)Cc2ccccc2N1CCCBr
Yield: 47.3 %

Procedure:
3-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.25 g, 0.9 mmol), 3-bromopropanol (0.094 mL, 1.1 mmol), diisopropylazodicarboxylate (0.21 mL, 1.08 mmol), and triphenylphosphine (0.28 g, 1.08 mol) in tetrahydrofuran (3 mL) were stirred at room temperature for 16 hours. The reaction was poured into saturated aqueous sodium chloride (20 mL) and extracted with ethyl acetate. The organics were dried over anhydrous sodium sulfate and concentrated on silica gel (0-100° C. ethyl acetate/hexane) to provide 1-(3-bromopropyl)-3-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.17 g, 47%) as a yellow solid:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C1COCC1.O>[CH2:15]([O:14][C:12]([N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 4-piperidone hydrochloride (79.0 g) in THF and water (4: 1,75 ml), was added 4N NaOH (105 ml) solution followed by benzyl chloroformate (66 ml) at 0° C. The resulting mixture was stirred at the same temperature for 1 h. At the end of this time, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulphate. The solvent was removed by distillation under reduced pressure to give 135 g (99.5%) of the title compound as a dark thick liquid.
Reaction SMILES: [Br:1]Br.[C:3]([N:7]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9](=[O:19])[CH2:8]1)([CH3:6])([CH3:5])[CH3:4].C([O-])(=O)C.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Br:1][C:16]1[CH:17]=[CH:18][C:11]2[NH:10][C:9](=[O:19])[CH2:8][N:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: CC(C)(C)N1CC(=O)Nc2ccccc2C1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CC(=O)Nc2ccc(Br)cc2C1=O
Temperature: 25 °C
Reaction time: 29 h
Yield: 64.3 %

Procedure:
Bromine (1.72 g, 10.8 mmol) is added to a mixture of 4-tert-butyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (1.0 g, 4.3 mmol) and sodium acetate (0.39 g, 4.8 mmol) in acetic acid. The reaction mixture is stirred at room temperature for 29 hours, concentrated in vacuo, diluted with ethyl acetate, washed sequentially with 0.1N sodium hydroxide solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue. Chromatography of the residue using silica gel and 20% to 25% ethyl acetate in hexanes solutions gives the title product as a white solid (0.86 g, mp 205°-208° C.).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:20]([NH:22][C@@H:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24](O)=[O:25])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][CH:40]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)Cl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([C:20](=[O:21])[NH:22][C@H:23]([C:24](=[O:25])[NH:38][C:39]3[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][CH:40]=3)[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(CO)cc1
Reactant: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(CO)cc1
Yield: 41.3 %

Procedure:
In a pear-shaped flask, the above synthesized (S)-2-[(S)-2-(9H-fluoren-9-ylmethoxy-carbonylamino)-3-phenyl-propionylamino]-hexanoic acid (10.72 g, 21 mmol, Eq: 1.00), (4-aminophenyl)methanol (2.717 g, 22 mmol, Eq: 1.03), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (7.994 g, 32 mmol, Eq: 1.50) were dissolved in CH2Cl2 (320 ml) and stirred over night under a balloon of Ar. The mixture was poured onto crashed ice/NH4Cl, extracted 2× with AcOEt, washed with H2O, dried over Na2SO4, and the volume reduced to ˜300 ml. The precipitate was filtered off and dryed to give 5.25 g of the title compound as light-brown solid. MS (ISP): (M+H) 606.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccc(F)cc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CS(=O)Cc2ccc(F)cc2)C1
Yield: 85.6 %

Procedure:
Using a similar procedure to that described in Example 107, step 1, (3R)-1-(tert-butoxycarbonyl)-3-[(4-fluorobenzylthio)methyl]pyrrolidine (0.5818 g, 1.79 mmol) was reacted with 57-86% 3-chloroperoxybenzoic acid (0.4477 g) in ethyl acetate (35ml) to give 0.5233 g (86%) of the title compound as a colourless oil. δH (360 MHz, CDCl3) 1.45 (9H, s), 1.66 (1H, m), 2.15 (1H, m), 2.54(1H, m), 2.63-2.71 (2H, m), 3.03 (1H, m), 3.31 (1H, m), 3.44 (1H, m), 3.65 (1H, m), 3.96 (2H, s), 7.08 (2H, t, J=8.6 Hz), 7.25-7.29 (2H, m). m/e (ES+) 342 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:26]=[C:27]=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:20]([NH:26][C:27](=[O:28])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCN=C=O
Reactant: CC1(C)CN(Cc2ccccc2)c2ccc(O)cc21
Product: CCCCCCNC(=O)Oc1ccc2c(c1)C(C)(C)CN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzyl-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with n-hexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (3.4 mg, 11%) having the following characteristics.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:13]3[O:14][CH3:15])[C:6]=2[N:7]=1.[CH3:23][O-:24].[Na+].CO>>[NH2:1][C:2]1[N:3]=[C:4]([O:24][CH3:23])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:13]3[O:14][CH3:15])[C:6]=2[N:7]=1
Reactant: C[O-]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c2c(Cl)nc(N)nc21
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1c(C)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC

Procedure:
A solution of the compound from Step A (50 mg, 0.15 mmol) in 0.5M NaOMe/MeOH (4 mL) was stirred at reflux temperature for 1.5 h. The mixture was cooled, mixed with silica gel and evaporated to dryness. The silica gel was loaded onto a silica gel column and eluted with a solvent system of CH2Cl2/MeOH: 30/1. The fractions containing the product were collected and evaporated to yield 2-amino-7-(2-O-methyl-β-D-ribofuranosyl)-4-methoxy-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (40 mg). This was mixed with 2 N aqueous NaOH (4 mL) and stirred at reflux temperature for 10 h. The mixture was cooled in ice bath, neutralized with 2 N aqueous HCl and evaporated. The solid residue was suspended in MeOH, mixed with silica gel and evaporated. The silica gel was loaded onto a silica gel column and eluted with a solvent system of CH2Cl2/MeOH: 5/1. Appropriate fractions were pooled and evaporated to give the title compound (40 mg) as a white solid.
Reaction SMILES: C([O:3][C:4]1(OCC)[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[CH2:5]1)[CH:12]=[CH:11][CH:10]=[CH:9]3)C.Cl>O1CCCC1>[C:4]1(=[O:3])[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[CH2:5]1)[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: CCOC1(OCC)Cc2ccc3ccccc3c21
Agent: Cl
Solvent: C1CCOC1
Product: O=C1Cc2ccc3ccccc3c21
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
10 g of the product obtained in Step 1 are treated at room temperature with 42 ml of 1N hydrochloric acid dissolved in 170 ml of tetrahydrofuran. After 1 hour 30 minutes' contact, the solvent is concentrated and the residue is poured into 170 ml of water. 6.9 g of a solid corresponding to the expected product are then isolated.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].[Cl:8][C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].Br.NCCBr>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:9]1[C:18]([C:19]2[O:20][CH2:2][CH2:1][N:3]=2)=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Agent: Br
Agent: NCCBr
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NCCO2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
At room temperature, 41.8 g (0.41 mol) of triethylamine and then 31.1 g (0.10 mol) of methyl 2-chloro-3-chlorocarbonyl-4-methylsulfonylbenzoate in 150 ml of toluene were added dropwise to 26.6 g (0.13 mol) of 1-amino-2-bromoethane hydrobromide in 5.00 ml of toluene. The mixture was heated under reflux for 5 hours and then stirred at room temperature for 12 hours, another 5.0 g (0.02 mol) of 1-amino-2-bromoethane hydrobromide were added and the mixture was heated under reflux for 7.5 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water, dried and concentrated. The residue was then recrystallized from methyl tert-butyl ether/ethyl acetate. 14.5 g (46% of theory) of methyl 2-chloro-4-methylsulfonyl-3-(4,5-dihydrooxazol-2-yl)benzoate were obtained.