Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[C:8](=O)[O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(n1)C(=O)OC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)COC2=O
Temperature: 15 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
A suspension of 2-methyl-furo[3,4-b]pyridine-5,7-dione (15 g, 92 mmol) in THF (100 mL) is treated with sodium borohydride (3.75 g, 99 mmol) at 15° C. under an argon atmosphere. The reaction mixture is then treated dropwise with acetic acid (12 g, 200 mmol) at 15° C. During this addition gas evolution is observed. The reaction mixture is stirred at 15° C. for 4 h and is then concentrated. The residue is treated with acetic acid (40 mL) and acetic anhydride (40 mL). The resulting solution is stirred at 100° C. for 3 h. The brown solution is cooled to room temperature and concentrated. The residue is treated with a 20% aqueous NaCl solution and extracted with chloroform. The organic extract is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated. The residue is purified by chromatography (silica gel, gradient elution, 5:1 hexane/ethyl acetate to 2:1 hexane/ethyl acetate). The product containing fractions are concentrated to give the title compound as a white solid (9.03 g, 44%).
Reaction SMILES: C(O[Li])(C)=O.[C:6]1([S:12]([O:15][C:16]2[C:25]([Br:26])=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([CH:27]=[O:28])=[N:23]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Si]([CH2:33][C:34]#[N:35])(C)(C)C>CN(C=O)C>[C:6]1([S:12]([O:15][C:16]2[C:25]([Br:26])=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([CH:27]([OH:28])[CH2:33][C:34]#[N:35])=[N:23]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Reactant: C[Si](C)(C)CC#N
Agent: [Li]OC(C)=O
Solvent: CN(C)C=O
Product: N#CCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.2 %

Procedure:
To a stirred solution of AcOLi (27 mg, 0.41 mmol) in DMF (1 mL) were added successively a solution of 8-bromo-2-formylquinolin-7-yl benzenesulfonate (1.60 g, 4.08 mmol) in anhydrous DMF (10 mL) and TMSCH2CN (465 mg, 4.11 mmol) at 0° C. And the reaction mixture was slowly warmed to room temperature. The mixture was stirred for 12 h at the same temperature and quenched with 15% citric acid (5.0 mL) and MeOH (5.0 mL). After the removal of MeOH in vacuo, the mixture was extracted with AcOEt and organic layer was washed with brine and dried over anhydrous Na2SO4, and evaporated. Purification by silica gel chromatography (Hexanes/EtOAc=2/1) gave S0187 as a yellow gum (0.89 g, 2.05 mmol, 50% yield). 13CNMR (ppm, 500 MHz, CDCl3, 298 K) δ: 159.989, 148.716, 144.388, 138.493, 135.675, 135.042, 129.556, 128.819, 128.189, 127.380, 123.481, 119.173, 118.419, 117.117, 68.926, 26.812. 1HNMR (ppm, 500 MHz, CDCl3, 298 K) δ: 8.262 (d, 1H, J=8.5 Hz), 7.968 (d, 2H, J=8.0 Hz), 7.836 (d, 1H, J=9.0 Hz), 7.716 (t, 1H, J=7.0 Hz), 7.633 (d, 1H, J=9.0 Hz), 7.588-7.545 (m, 3H), 5.224−5.188 (m, 1H), 5.126 (d, 1H, J=6.0 Hz), 3.031−2.929 (m, 2H). MS-ESI (m/z): [M+H]+ calculated for C18H14BrN2O4S, 433.0 (79Br) and 435.0 (81Br); found 432.9 (79Br) and 434.9 (81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13](O)[CH3:14])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1(C)C=CC=CC=1>[N:35]([CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:9]=1)[CH3:14])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To the product from Example 164b (0.30 g, 1.0 mmol) in toluene (20 mL) was added diphenylphosphoryl azide (0.36 g 6.26 mmol), followed by 1,8-diazabicyclo[4.3.0]undec-7-ene (0.19 g, 1.3 mmol). The mixture is stirred at 25° C. for 18 h. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers are washed with 5% HCl, sat. NaCl (1×), dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by silica gel chromatography, eluting with hexanes/ethyl acetate/methanol (85:15:5) to provide the title compound (300 mg, 94%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=O)[O:23]C(C)(C)C)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([O:21][C:22]([N:16]1[CH:14]2[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15]2)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: c1ccc(CN2CC3CCCC(C2)N3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCCC1CN(Cc1ccccc1)C2
Temperature: 23 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
To a solution of 3-benzyl-3,9-diaza-bicyclo[3.3.1]nonane (755 mg, 3.49 mmol, 1.0 eq) in CH2Cl2 (10 mL) was added di-tert-butylcarbonate (990 mg, 4.54 mmol, 1.3 eq) and triethylamine (0.730 mL, 5.24 mmol, 1.5 eq) and the mixture stirred for 16 hours at 23° C. The reaction mixture was diluted with CH2Cl2 and washed with water. The organic was collected and dried (Na2SO4), filtered, and concentrated to an oil. The crude was purified using silica gel chromatography eluting with ethyl acetate/heptane mixtures which gave the desired product as a colorless oil (477 mg) in 41% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9H) 1.51-1.64 (m, 1H) 1.64-1.75 (m, 2H) 1.75-1.93 (m, 2H) 2.21-2.39 (m, 2H) 2.79-2.92 (m, 3H) 3.40 (s, 2H) 4.06 (br. s., 1H) 4.18 (br. s., 1H) 7.21-7.30 (m, 1H) 7.34 (d, J=4.55 Hz, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([NH:9][CH3:10])[C:7]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+].[H][H]>[Ni].O>[CH3:10][NH:9][C:8]1[CH:11]=[C:4]([CH:5]=[CH:6][C:7]=1[S:12]([OH:15])(=[O:14])=[O:13])[NH2:1]
Reactant: [H][H]
Reactant: CNc1cc([N+](=O)[O-])ccc1S(=O)(=O)O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1cc(N)ccc1S(=O)(=O)O

Procedure:
23.2 g of 5-nitro-N-methylaniline-2-sulfonic acid were added to 300 g of water. The pH was then adjusted to from 5. 0 to 5.5 with sodium hydroxide solution, 2 g of Raney nickel were added and hydrogenation was carried out under atmospheric pressure at 30° C. After hydrogen uptake had ceased, the catalyst was filtered off, the pH of the filtrate was adjusted to 0.5 to 1.0 with hydrochloric acid, and the precipitated 3-(N-methylamino)aniline-4sulfonic acid was isolated by filtration.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19]CCF)[N:12]=[CH:11][N:10]=[C:9]2[NH:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[CH:26][C:25]=1[F:32])=[O:4].ClC1C(Cl)=CC(NC2C3C(=CC(OCCO[CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][F:71])=C(N)C=3)N=CN=2)=C(F)C=1.CCN(C(C)C)C(C)C.ClCC(Cl)=O>C1COCC1>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][F:71])[N:12]=[CH:11][N:10]=[C:9]2[NH:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[CH:26][C:25]=1[F:32])=[O:4]
Reactant: Nc1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCOCCOCCF
Reactant: O=C(CCl)Nc1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCF
Agent: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCOCCOCCF

Procedure:
Compound 1c was prepared as described hereinabove for Compound 1a, using Compound 38c (0.13 gram, 0.21 mmol), DIPEA (0.43 mmol, 75.1 μl) and chloroacetylchloride (0.43 mmol, 34.3 μl in THF (18 ml), yielding 0.03 gram of the product (21% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12]2)[C:3]=1[C:4]#[N:5].[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>>[S:17]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12]2)[C:3]=1[C:4]#[N:5])(=[O:20])(=[O:19])[NH2:18]
Reactant: NS(=O)(=O)Cl
Reactant: CC1CCC(Oc2cccc(N)c2C#N)C1
Product: CC1CCC(Oc2cccc(NS(N)(=O)=O)c2C#N)C1
Yield: 52 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(3-methylcyclopentyloxy)benzonitrile (Example 251b) and sulfamoyl chloride in 52% yield. MS 296 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[N:7]=1.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[N:7]=1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2[nH]1
Reactant: NC1CCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1cc2c(NC3CCC3)nc(Cl)nc2[nH]1
Yield: 44.9 %

Procedure:
A solution of 2,4-dichloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (190 mg, 0.94 mmol), cyclobutylamine (0.160 mL, 1.88 mmol) and triethylamine (0.200 mL, 1.44 mmol) in nBuOH (6 mL) was stirred at 70° C. overnight. It was then purified by HPLC to give 2-chloro-N-cyclobutyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=1.O>C1(C)C=CC=CC=1>[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 38.7 %

Procedure:
3.98 g (0.02 mol) of 1-benzyl-4-hydroxy-piperidine in 70 ml of toluene were treated with 0.624 g of NaH (50%) and heated at reflux for 1 1/2 hr. while gassing with argon. Subsequently, 3.32 g (0.022 mol) of methyl 4-amino-benzoate dissolved in 80 ml of toluene were added dropwise over 1/2 hr. and the mixture was heated at reflux for a further 2 hrs. The suspension obtained was added to 400 mi of water and the mixture was stirred. The precipitate was filtered off under suction and washed with toluene and hexane. The organic phase of the filtrate was separated, washed three times with water, dried over MgSO4 and evaporated and the residue was combined with the filter material. Chromatography was carried out over silica gel with chloroform as the eluent and recrystallization was carried out from ethyl acetate/hexane. 2.4 g (38.7%) of 1-benzyl-piperidin-4-yl 4-amino-benzoate were obtained as colorless crystals; m.p. 119°-120° C.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:9]([O:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15])[CH3:10]>>[CH2:9]([O:11][P:12]([CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:13][CH2:14][CH3:15])=[O:16])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)P(=O)(OCC)OCC

Procedure:
Ethyl 2-bromopropanoate (30.0 g.) and triethylphosphite (70.0 g.) were heated overnight at 150° C. under an air condenser. The resulting crude mixture was purified by distillation, the ethyl 2-(diethylphosphono)propanoate was collected at 66°-68° C. at 0.3-0.5 mm.Hg.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:31])(=[O:30])[C:13]=2[CH:32]=1)=[O:8].N1C=CC=CC=1>ClCCl>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:26]([C:1](=[O:3])[CH3:2])[CH2:27][CH2:28]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:31])[C:13]=2[CH:32]=1)=[O:8]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(C)=O)CC3)cc(Cl)c1O2
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Acetyl chloride (0.15 mL, 2.06 mmol) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) in dichloromethane (15 mL) and stirred at 20° C., for 10 min. To this, pyridine (0.33 mL, 4.12 mmol) was added and the mixture was stirred further for 18 h. The solvent was removed from the mixture and water (15 mL) was added. The pH of the reaction mixture was adjusted to 3 using aqueous hydrochloric acid (10%). The solid obtained was filtered and the crude obtained was purified by column chromatography (silica gel, 2% methanol in chloroform) to obtain the title compound. Yield: 0.3 g, (91%); 1H NMR (DMSO-d6, 300 MHz): δ 2.02 (s, 3H, CH3), 2.63 (s, 3H, CH3), 3.15 (s, 2H, CH2), 3.17 (s, 2H, CH2), 3.55 (s, 4H, 2CH2), 3.85, (s, 3H, OCH3), 5.16 (s, 2H, CH2), 7.09 (d, 1H, Ar), 7.15 (d, 1H, Ar), 8.08 (t, 1H, Ar), 8.15 (t, 1H, Ar); MS: m/e (ES+) 479 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([CH3:18])(O)[CH:13]([CH2:19][CH3:20])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH2:19]([C:13]1[CH2:12][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][C:14]=1[CH3:18])[CH3:20]
Reactant: CCC1CC(CCOCc2ccccc2)CCC1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Solvent: O
Product: CCC1=C(C)CCC(CCOCc2ccccc2)C1

Procedure:
A mixture of 5-(2-benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester in anhydrous MeOH (10 mL) was reacted with NaOMe solution (16.6 mL, 8.28 mmol) at rt for 15 min. Iodoethane (2.76 mL, 34.5 mmol) was added via syringe and the mixture was stored at rt for 48 h. Another portion of NaOMe (8.3 mmol) and EtI (35 mmol) was added and the mixture was allowed to react until the starting material was not present (by TLC). The solution was quenched with an aqueous work-up and the resultant residue was purified by chromatography to yield 5-(2-benzyloxy-ethyl)-1-ethyl-2-oxo-cyclohexanecarboxylic acid methyl ester (Intermediate K2, 1.87 g (86%). The keto-ester (Intermediate K2) was heated at 90° C. in 10% KOH (100 mL) for 10 h, then 6 h at rt. The mixture was cooled to 0° C. and acidified with HCl. The solution was warmed to 40° C. for 15 min. and then stored at rt for 2 h. The mixture was neutralized to pH 7 with NaOH and the organic material was recovered by extraction with chloroform. The resulting 4-(2-benzyloxy-ethyl)-2-ethyl-cyclohexanone (Intermediate K3) was isolated by standard work-up and used without further purification (88%). Intermediate K3 (1.36 g, 5.24 mmol) was dissolved in THF (75 mL) and treated with MeMgBr (2.62 mL, 7.9 mmol) at 0° C. and reacted at rt for 1 h. The organic material was isolated from an aqueous, acidic work-up and purified by chromatography to give 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol 1.36 g (94%). 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol (1.39 g, 5.04 mmol) and TsOH—H2O (0.48 g, 2.52 mmol) were heated to reflux in benzene (˜100 mL) for 18 h in the presence of MgSO4 (˜250 mg). After an aqueous work-up and chromatographic purification, the product [2-(3-ethyl-4-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate K4) was isolated as a pale yellow oil 0.912 g (71%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[C:2]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Nc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc2)cc1
Reaction time: 0.25 h
Yield: 192.2 %

Procedure:
Bis(4-bromophenyl)amine (4.0 g, 12.3 mmol) and phenylboronic acid (4.0 g, 32.7 mmol) were mixed in 250 mL of toluene and 60 mL of ethanol. The solution was bubbled with nitrogen while stirring for 15 minutes. Pd(PPh3)4 (1.4 g, 1.23 mmol) and K3PO4 (13.5 g, 64 mmol) were added in sequence. The mixture was heated to reflux overnight under nitrogen. After cooling, the reaction mixture was filtered through filter paper and the solvent was then evaporated. The solid was redissolved in nitrogen-purged hot toluene and was filtered through a Celite®/silica pad when the solution was still hot. The solvent was then evaporated. The white crystalline solid was washed by hexane and air dried to obtain 3.8 g of product.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:5]1(=[O:22])=[O:21].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.Cl>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH2:9][N:4]([CH2:3][CH2:2][NH:26][CH:23]2[CH2:25][CH2:24]2)[S:5]1(=[O:22])=[O:21]
Reactant: NC1CC1
Reactant: O=S1(=O)N(CCBr)Cc2ccccc2N1c1ccccc1F
Agent: Cl
Product: O=S1(=O)N(CCNC2CC2)Cc2ccccc2N1c1ccccc1F

Procedure:
In an analogous manner to Example 11 step 5, 3-(2-bromoethyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.96 g, 0.25 mmol) was reacted with cyclopropylamine and then treated with HCl to afford N-{2-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]ethyl}cyclopropanamine as a white solid:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[CH2:25][CH2:26]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)c1ccccc1F
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccccc3F)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
0.29 g of 2-fluoro-benzoic acid (2.03 mmol) and 0.7 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.03 mmol) were dissolved in 25 ml of dichloromethane. 1.04 g of diisopropylethylamine (8.04 mmol), 0.19 g of hydroxybenzotriazole (HOBt, 1.4 mmol), and 0.46 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.4 mmol) were added at 0° C. and the reaction mixture was stirred for 16 h at room temperature. 25 ml of dichloromethane were added, the organic layer washed with aqueous saturated sodium chloride, the aqueous phase re-extracted once with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (5%). Fractions containing the product were combined. The solvent was evaporated to yield 0.84 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:50]([C:52]1[CH:60]=[C:59]([CH3:61])[C:55]([C:56](O)=[O:57])=[C:54]([CH3:62])[CH:53]=1)#[N:51].CCN(C(C)C)C(C)C>CN(C=O)C>[C:50]([C:52]1[CH:60]=[C:59]([CH3:61])[C:55]([C:56]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:7][CH2:8][CH:9]([N:12]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11]2)[CH3:5])=[O:57])=[C:54]([CH3:62])[CH:53]=1)#[N:51]
Reactant: Cc1cc(C#N)cc(C)c1C(=O)O
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C#N)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (1.00 g, 2.62 mmol), EDCI (0.55 g, 2.88 mmol) and HOBT (0.39 g, 2.88 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 4-cyano-2,6-dimethyl-benzoic acid (0.50 g, 2.88 mmol) followed by DIPEA (1.14 mL, 6.55 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v) afforded 4-cyano-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (0.77 g, 54%) as a white foam. 1H NMR (CDCl3) δ 0.98-1.04 (d+m, 4H), 1.22 (m, 1H), 1.54 (m, 1H), 1.73-1.82 (m, 3H), 2.16 (t, 1H), 2.33 (s, 3H), 2.36 (s, 3H), 2.40 (m, 1H), 2.52 (m, 1H), 2.69-2.88 (m, 3H), 3.21 (m, 1H), 3.33 (m, 1H), 3.73 (s, 3H), 3.77 (m, 1H), 3.96 (s, 2H), 6.63 (d, 2H, J=9.0 Hz), 6.73 (d, 2H, J=9.0 Hz), 7.05 (d, 1H, J=6.0 Hz), 7.27 (s, 2H), 7.84 (br s, 1H), 8.25 (s, 1H), 8.31 (d, 1H, J=6.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[CH2:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O>[Cl:1][C:2]1[N:11]=[C:10]([O:20][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOc1nc(Cl)nc2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
7.3 g of 2,4-dichloroquinazoline (J. Chem. Soc., 1947, 775) was suspended in 40 ml of N,N-dimethylformamide, and with ice cooling, 1.9 g of sodium hydride (oily, 60 %) was added. A solution of 3.7 g of l-pentanol in 5 ml of N,N-dimethylformamide was added dropwise over 5 minutes, and then further stirred at 50° C. for 1 hour. After cooling, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography [eluted with hexane/ethyl acetate (8:1, v/v)] to give 8 g of 2-chloro-4-pentyloxyquinazoline. A portion of this produce was recrystallized from hexane to give a product having the following physical property values.