Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:19][O:20][CH2:21]Cl>C(OCC)(=O)C.O>[CH3:19][O:20][CH2:21][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[N:6]1
Reactant: COCCl
Reactant: O=[N+]([O-])c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COCn1cc([N+](=O)[O-])nn1
Yield: 61.5 %

Procedure:
4-nitro-1H-1,2,3-triazole (6.468 g, 56.707 mmol) and potassium carbonate (15.683 g, 113.472 mmol) were added into 150 mL acetone. Chloromethyl methyl ether (4.74 mL, 62.407 mmol) was added dropwise into the above mixture under ice bath. After completion, water and ethyl acetate were added into the reaction solution. Phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, chromatographed on a silica gel column (ethyl acetate:petroleum ether=1:5) to obtain 1-(methoxymethyl)-4-nitro-1H-1,2,3-triazole, as 5.517 g of a light yellow liquid, at a yield of 61.5%.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10](=[O:32])[N:11]1[CH2:20][C:19]2[N:15]([CH:16]=[N:17][C:18]=2[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[C:14]2[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=2[CH2:12]1)(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[NH2:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:11]1[CH2:20][C:19]2[N:15]([CH:16]=[N:17][C:18]=2[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[C:14]2[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=2[CH2:12]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1Cc2ccccc2-n2cnc(C(=O)N3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC(=O)N1Cc2ccccc2-n2cnc(C(=O)N3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To solution of (R)-[3-oxo-3-[3-(pyrrolidine-1-carbonyl)-4H,6H-2,5,10b-triaza-benzo-[e]azulen-5-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (45 mg, 0.08 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.24 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction, as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford a gummy solid which was crystallized from hexane to afford trifluoroacetic acid salt of (R)-3-amino-1-[3-(pyrrolidine-1-carbonyl)-4H,6H-2,5,10b-triaza-benzo[e]azulen-5-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one (40 mg, 86%)
Reaction SMILES: N1([CH2:6][CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[C:21]([C:31]([NH2:33])=[O:32])[CH:22]=[C:23](C5C=CSC=5)[CH:24]=4)[NH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])CCCC1.[Cl:34][C:35]1[S:39][C:38](B(O)O)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].O1[CH2:54][CH2:53]OCC1>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>[Cl:34][C:35]1[S:39][C:38]([C:23]2[CH:24]=[C:25]3[C:20](=[C:21]([C:31]([NH2:33])=[O:32])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:14]2[CH2:13][CH2:12][N:11]([S:8]([CH2:7][CH2:6][CH2:16][N:11]3[CH2:54][CH2:53][CH2:13][CH2:12]3)(=[O:10])=[O:9])[CH2:16][CH2:15]2)=[CH:37][CH:36]=1
Reactant: C1COCCO1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCN4CCCC4)CC3)c[nH]c12
Reactant: OB(O)c1ccc(Cl)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)c1cc(-c2ccc(Cl)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12

Procedure:
The title compound was prepared following the general procedure described in intermediate 16. Thus, 15-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (95 mg, 0.19 mmol) in dioxane (3 mL) and water (1 mL), 5-chloro-2-thienylboronic acid (123 mg, 0.76 mmol), Pd(PPh3)4 (22.2 mg, 10%) and potassium carbonate (211 mg, 1.52 mmol) in dioxane (3.0 mL) and water (1.0 mL) were reacted to form the desired product which was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (11 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)(=[O:14])=[O:13].O>CS(C)=O>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(Cl)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 93.1 %

Procedure:
To a solution of 7.41 g (0.0576 mole) of 4-chlorophenol dissolved in 150 ml of DMSO was added 2.30 g (0.0576 mole) of NaOH. The mixture was heated to 60° C. and 10.0 g (0.0524 mole) of 4-chlorophenyl methyl sulfone was added. The reaction mixture was heated at 160° C. for 3 hrs and cooled. The mixture was poured into a solution of 400 ml of 2 Normal (N) aqueous NaOH and 300 ml of water. The crystalline product was collected by filtration, washed well with water, and dried, which gave 13.8 g (93.2% yield) of product, m.p. 109°-111° C. Recrystallization from ethanol afforded purified 4-(4-(methylsulfonyl)phenoxy)-1-chlorobenzene, mp 111°-112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[C:2]1([NH:1][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[CH:19]([CH3:20])[CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)cccc21
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Nc3ccccc3)cccc21
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Aniline (328 μl, 3.6 mmol) was added to a room temperature mixture of 4-bromo-1-triisopropylsilanyl-1H-indole (1.06 g, 3 mmol), tris(dibenzylideneacetone)dipalladium 2-(dicyclohexylphosphino)-2,4,6-triisopropyl-1,1′-biphenylphosphine (Pd2(dba)3, 27.5 mg, 0.03 mmol), (72 mg, 0.05 mmol) and K2CO3 (1.04 g, 7.5 mmol) in t-BuOH (14 ml). The reaction mixture was stirred at 110° C. for 4 hours. The reaction was cooled, and the solid was filtered off. The filtrate was concentrated and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording the compound XXI as a yellow oil in quantitative yield (1.09 g).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH3:49])[CH3:48])C1C=CC=CC=1.Cl>CO.[Pd]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@@H:12]2[O:11][C:10]([CH3:49])([CH3:48])[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@H:13]2[OH:23])=[CH:32][C:33]=1[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=1.[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:12]2[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C:10]3([CH2:49][CH2:48]3)[O:11]2)=[CH:32][C:33]=1[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(C)(C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3OC(C)(C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Product: CCOc1ccc(Cc2cc([C@@H]3OC4(CC4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the above crude mixture of (3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2,2-dimethyl-tetrahydro-pyran (˜100 mg, 0.14 mmole) in methanol (3 mL), 10% Pd/C (100 mg) and 2 drops of con. HCl added and stirred under hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered through cetlie bed, washed with methanol (20 mL). The crude product was purified by preparative chiral HPLC to furnish 10 mg of (3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2,2-dimethyl-tetrahydro-pyran-3,4,5-triol (Ex. 11) and 20 mg of (5S,6R,7R,8S)-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]octane-6,7,8-triol (Ex. 2).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=[O:4].[CH3:23][S:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH2:29][C:28]4[CH:31]=[CH:32][C:25]([S:24][CH3:23])=[CH:26][CH:27]=4)[CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=[O:4]
Reactant: CSc1ccc(C=O)cc1
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3CCCNC3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CSc1ccc(CN2CCCC(Nc3ccc4c(cnn4C(=O)C(C)(C)C)c3)C2)cc1
Yield: 71.6 %

Procedure:
Into a 25 mL round bottom flask were combined 2,2-dimethyl-1-(5-(piperidin-3-ylamino)-1H-indazol-1-yl)propan-1-one (0.250 g, 0.8 mmol), 1,2-dichloroethane (5 mL), 4-(methylthio)benzaldehyde (0.127 g, 0.8 mmol), glacial acetic acid (50 μL, 0.8 mmol), and sodium triacetoxyborohydride (0.229 g, 1.1 mmol). The reaction was evacuated and refilled with nitrogen. The reaction was monitored by HPLC and was complete upon the disappearance of the starting amine. The reaction was diluted with saturated sodium bicarbonate (10 mL) and dichloromethane (5 mL). After mixing, the organic phase was isolated, dried over MgSO4, filtered and concentrated to give the crude product. Chromatography of the residue on silica gel gave the title compound as an off-white solid (250 mg, 69%).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[CH2:8][CH2:7]1)=O)C.[OH-].[Na+]>Cl>[NH:6]1[CH2:7][CH2:8][CH:9]([NH:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:17][CH2:18]2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCC(N[C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](NC2CCNCC2)CC1

Procedure:
. A stirred solution of 1.2 g of 1,3-dihydro-1-{trans-4-[1-ethoxycarbonyl-4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one in 20 mL of 6N HCl was heated to reflux for 12 h, cooled and basified with 6N NaOH. The basic mixture was extracted with 2×50 mL portions of chloroform. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. After drying overnight under vacuum, there was obtained 0.51 g of 1,3-dihydro-1-{trans -4-[4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 7.33 (m, 1H), 7.11 (m, 1H), 7.04 (m, 2H), 4.37 (m, 1H), 3.16 (m, 3H), 2.61-2.52 (m, 5H), 2.0 (d, 2H), 1.86 (d, 2H), 1.64 (m, 4H), 1.3 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[CH3:22][N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=1>CCOCC>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:34][C:31]1[CH:30]=[CH:29][C:28]([CH:24]2[CH2:25][CH2:26][CH2:27][N:23]2[CH3:22])=[CH:33][N:32]=1
Reactant: CN1CCCC1c1ccc(N)nc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CCCC1c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(I)cc32)nc1
Temperature: 125 °C

Procedure:
A mixture of (E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (696 mg, 2.12 mmole), dimethylformamide (15 mL), and 5-(1-methylpyrrolidin-2-yl)pyridin-2-amine (375 mg, 2.12 mmole) is heated at 125° C. for four hours. The reaction mixture is cooled, diluted with ether, filtered, washed with fresh ether and dried to give a yellow solid, 580 mg, (58%), mp 174-206° C. dec; MS (ES+): m/z 475.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[S:14]([C:17]1[C:25]2[C:21](=[N:22][S:23][N:24]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:2]=1[NH:1][S:14]([C:17]1[C:25]2=[N:24][S:23][N:22]=[C:21]2[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: COC(=O)c1ccc(Br)cc1N
Product: COC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 75 %

Procedure:
The title compound (3.95 g, 75%) was prepared from methyl 2-amino-4-bromobenzoate and 4-chlorosulfonyl-2,1,3-benzothiadiazole as in Example 1, Part A. MS (ESI−): mass calcd. for C14H10BrN3O4S2, 426.9; m/z found, 426 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.34 (br s, 1H), 8.40 (dd, J=7.0, 0.9, 1H), 8.24 (dd, J=8.8, 0.9, 1H), 7.92 (d, J=1.8, 1H), 7.74 (dd, J=8.8, 7.0, 1H), 7.72 (d, J=8.5, 1H), 7.10 (dd, J=8.5, 1.8, 1H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][N-:7][CH2:8][CH2:9][CH3:10].O=P(Cl)(Cl)Cl.[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=1.[OH-].[Na+].O>ClCCCl>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([N:26]=[C:8]([NH:7][CH2:6][CH2:5][O:4][C:3]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=2[Cl:1])[CH2:9][CH3:10])=[C:24]([CH3:29])[CH:23]=1
Reactant: CCC[N-]CCOc1ccc(Cl)cc1Cl
Reactant: Cc1cc(Cl)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCC(=Nc1ccc(Cl)cc1C)NCCOc1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
A mixture of 19.5 g (0.075 mole) of N-(2-(2,4-dichlorophenoxy)ethyl)propylamide, 11.4 g (0.075 mole) POCl3 and 250 mls of 1,2-dichloroethane was stirred at 60° C. for six hours. The mixture was cooled to 25° C., whereupon 10.4 g (0.075 mole) of 4-chloro-2-methylaniline was added thereto. An exotherm was noted. The mixture was refluxed for 10 hours and allowed to cool. The product mixture was made basic with a 20% NaOH water solution. The product layer was separated, washed once with 200 ml of water, dried over sodium sulfate, filtered and distilled under reduced pressure to give 65% yield (based on the amide) of the desired product, a thick oil, b.p. 142° C./1.3 mm Hg . NMR confirmed the assigned structure: ##STR4##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(-c2cccc(O)c2)c2c1C(=O)NC2
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccc(N)c3c2CNC3=O)c1
Yield: 59.5 %

Procedure:
In a similar manner to Step 1 of Example 304, 7-amino-4-(3-hydroxyphenyl)isoindolinone (137 mg, 0.569 mmol) was dissolved in acetonitrile (7.0 mL), and the solution was treated with tert-butyldimethylsilyl chloride (155 mg, 1.02 mmol) and DBU (0.154 mL, 1.02 mmol), followed by purification by flash column chromatography (chloroform) to obtain 7-amino-4-(3-tert-butyldimethylsilyloxyphenyl)isoindolinone (120 mg, yield 59%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:20]2[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 0.10 g, 0.40 mmol), 2-chloro-5-fluoro-pyrimidine (0.053 g, 0.40 mmol) and triethylamine (0.11 mL, 0.81 mmol) in DMF (0.5 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (10 CH2Cl2:1-20 IPA:89-70 hexane) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):345.29
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].Br[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].CN1CCOCC1>O1CCOCC1>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NCC(=O)OCc1ccccc1)C(C)C
Yield: 21.9 %

Procedure:
A solution of 2.12 g (12.6 mmol) of L-valine methyl ester hydrochloride, 2.0 ml (12.6 mmol) of benzyl bromoacetate, and 3.5 ml (31 mmol) of 4-methylmorpholine in 100 ml of dioxane was heated at reflux for 4 h. After being allowed to cool, the solution was concentrated in vacuo and partitioned between ether and water. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography on silica gel using 20% ethyl acetate in hexane provided 0.77 g (22%) of the desired compound as a colorless oil (Rf 0.24, 20% ethyl acetate in hexane). 1H NMR δ 0.95 (d, J=7 Hz, 6H), 1.96 (br, 1 H), 1.98 (octet, J=7 Hz, 1H), 3.08 (d, J=6 Hz, 1H), 3.43 (AA',2H), 3.71 (s, 3H), 5.16 (s, 2H), 7.36 (m, 5 H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[N:21]=[C:2]([NH:22][C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)=[O:28])=[CH:25][C:24]=3[O:39][CH3:40])[N:3]=[CH:4][C:5]1=2
Reactant: CC1CN(c2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(c1ccccc1)CC(C)C(=O)N2C
Yield: 60.2 %

Procedure:
A solution of 0.050 g (0.000165 mole) of (rac)-2-chloro-5,7-dimethyl-9-phenyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-51), 0.043 g (0.000165 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.049 (0.00025 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol (4.0 mL) was heated at 180 degrees for 2 hours in a microwave reactor. The cooled reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75:25), to give 0.0526 g of (rac)-4-(5,7-dimethyl-6-oxo-9-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-51) as white powder. HRMS (ES+) m/z Calcd for C29H35N7O3+H [(M+H)+]: 530.2874. Found: 530.2870.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:9]([Cl:15])=[CH:10][CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[ClH:15].[Cl:15][C:9]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[C:7]2[C:12]([CH2:13][CH2:14][C@H:5]([CH2:4][NH2:1])[O:6]2)=[CH:11][CH:10]=1
Reactant: Cc1ccccc1-c1c(Cl)ccc2c1O[C@@H](CN=[N+]=[N-])CC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1c(Cl)ccc2c1O[C@@H](CN)CC2
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a solution of (2R)-2-(azidomethyl)-7-chloro-8-o-tolylchroman (0.5 g, 1.6 mmol) in THF (15 mL) and water (0.5 mL) was added polymer-bound triphenylphosphine (3 mmol/g, 0.8 g, 2.4 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was filtered through a pad of Celite and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 10% methanol in methylene chloride provided 0.15 g of the title compound as a colorless oil. The oil was dissolved in ethyl acetate (5 mL) and to which hydrogen chloride (1.0 M in ethyl ether, 1.5 mL, 1.5 mmol) was added, solvent was removed and the solid was washed with ethyl ether (3×5 mL) to provide 0.13 g of ((2R)-7-chloro-8-o-tolylchroman-2-yl)methanamine hydrochloride as a white solid salt, mp 155° C.; MS (APPI) m/z 288 ([M+H]+); [α]D25=−55° (c=1% SOLN, MeOH).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33](O)=[O:34])[C:27]=2[O:26][CH2:25]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:33]([C:32]3[C:27]4[O:26][CH2:25][O:24][C:28]=4[CH:29]=[CH:30][CH:31]=3)=[O:34])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: O=C(O)c1cccc2c1OCO2
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCO4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with benzo[1,3]dioxole-4-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=480.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])C.Br[O-:19].[Na+]>O1CCOCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:19])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: [O-]Br
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
18 g of 4-acetyl-4'-methoxybiphenyl was dissolved in 285 ml of dioxane and oxidized with a dilute sodium hypobromite. The product was recrystallized in a mixture of ethanol and acetic acid to obtain 4'-methoxybiphenyl-4-carboxylic acid.