Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][C:11]=3[C:12](=[O:15])[C:13]=2[OH:14])=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][C:11]=3[C:12](=[O:15])[C:13]=2[O:14][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc2oc(-c3ccc(O)cc3)c(O)c(=O)c2c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1ccc2oc(-c3ccc(O)cc3)c(OCc3ccccc3)c(=O)c2c1
Yield: 84 %

Procedure:
Prepared analogously to Example 5d, starting from 2-(4-hydroxyphenyl)-3-hydroxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 84%; Rf (9/1 Chloroform/Methanol): 0.59, 1H-NMR (d6-DMSO): 10.38 (s broad, 1H), 8.40 (d, 1H), 8.1-7.9 (m, 3H), 7.70 (d, 1H); 7.55-7.25 (m, 10H); 7.17 (d, 2H); 5.22 (s, 2H), 5.07 (s, 2H); 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])[C:10]([Cl:24])=[N:9][C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]1)[C:2]#[C:3][CH3:4].[C:39](=O)([O-])[O-:40].[K+].[K+].Cl.NC1CCCN(C2N(CC#CC)C3C(=O)N(CC4C=CC=CC=4C#N)C(C#N)=NC=3N=2)C1>CO>[ClH:24].[NH2:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:6]2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:13]3[C:12](=[O:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]#[N:23])[C:10]([O:40][CH3:39])=[N:9][C:8]=3[N:7]=2)[CH2:26]1
Reactant: O=C([O-])[O-]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)n(Cc3ccccc3C#N)c(=O)c21
Agent: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CC#CCn1c(N2CCCC(N)C2)nc2nc(OC)n(Cc3ccccc3C#N)c(=O)c21
Reaction time: 3 h

Procedure:
A mixture consisting of 15 mg of t-butyl [1-[7-(2-butynyl)-2-chloro-1-(2-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate, 20 mg of anhydrous potassium carbonate and 0.2 ml of methanol was stirred for three hours. Subsequent steps were carried out according to the same procedure as used in Examples 242 (f) and (g). Thus, the title compound was synthesized.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[NH2:7][C:8]1[N:13]=[C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([C:24]([O:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[CH2:21]3)=[CH:16][CH:15]=2)[CH:11]=[C:10]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:9]=1>>[NH2:7][C:8]1[N:13]=[C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([C:24]([O:26][CH:27]4[CH2:32][CH2:31][N:30]([C:2]([O:4][CH3:5])=[O:3])[CH2:29][CH2:28]4)=[O:25])[CH2:21]3)=[CH:16][CH:15]=2)[CH:11]=[C:10]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:9]=1
Reactant: COC(=O)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: COC(=O)N1CCC(OC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from methyl chloroformate and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=510.2.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])[CH:7]=1)=[O:5])C.[CH2:23]([CH2:25][NH2:26])[OH:24].N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[OH:24][CH2:23][CH2:25][NH:26][C:4]([C:6]1[O:10][N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])[CH:7]=1)=[O:5]
Reactant: CCCCc1noc(C)c1/C=C/c1cc(C(=O)OCC)on1
Reactant: NCCO
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1/C=C/c1cc(C(=O)NCCO)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To a solution of 3-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-isoxazole-5-carboxylic acid ethyl ester (70 mg, 0.23 mmol) and ethanolamine (28 mg, 0.46 mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (10 mg, 0.07 mmol) and the reaction stirred under argon overnight at room temperature. Then silica (1 g) was added and the mixture evaporated and the residue purified by chromatography (silica, dichloromethane:methanol=9:1 to 7:3) to afford the title compound (20 mg, 27%) which was obtained as a white solid. MS: m/e=320.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:16])(=[N:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:4][CH:3]=1.[Br:17][C:18]1[C:19]([NH:25][C@H:26]([CH3:31])[C:27]([CH3:30])([OH:29])[CH3:28])=[N:20][C:21](Cl)=[N:22][CH:23]=1.O.Cl>C(#N)C.O1CCOCC1>[Br:17][C:18]1[C:19]([NH:25][C@H:26]([CH3:31])[C:27]([OH:29])([CH3:28])[CH3:30])=[N:20][C:21]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:16])(=[N:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:4][CH:3]=2)=[N:22][CH:23]=1
Reactant: C[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)O
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(Br)c(N[C@H](C)C(C)(C)O)n2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
600 mg (2.48 mmol) of (RS)-S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methyl sulfoximide and 610 mg (2.07 mmol) of (R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol in 8 ml of acetonitrile are mixed with 0.52 ml of water and 0.52 ml of a 4N solution of HCl in dioxane. The batch is stirred for 24 hours at 60° C. and then concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 8:2). 649 mg (1.30 mmol, corresponding to 53% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:52])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]4[C:45]5=[N:46][O:47][N:48]=[C:44]5[C:43]([N+:49]([O-:51])=[O:50])=[CH:42][CH:41]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:52])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]4[C:45]5=[N:46][O:47][N:48]=[C:44]5[C:43]([N+:49]([O-:51])=[O:50])=[CH:42][CH:41]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 28.7 %

Procedure:
To a slurry of N-(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)-6-(7-nitrobenzofurazan-4-ylamino)hexanamide (22, 88 mg, 0.097 mmol) and K2CO3 (134 mg, 0.970 mmol) in N,N-dimethylformamide (8 mL) and tetrahydrofuran (2 mL), was added thiophenol (79 μL, 0.767 mmol). After 18 h at 23° C., the suspension was filtered and solvent removed in vacuo. Purification by preparative reverse-phase HPLC (gradient: 69.9% MeCN, 30% H2O, and 0.1% TFA to 99.9% MeCN, 0% H2O, and 0.1% TFA over 10 min; retention time=7.7 min) afforded 8 (20 mg, 29%) mp 78-80° C.; 1H NMR (500 MHz, DMSO d6) δ 9.54 (br s, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.43 (br s, 1H), 7.99 (t, J=5.8, 1H), 6.38 (d, J=9.0 Hz, 1H), 5.34 (br s, 1H), 3.43 (m, 1H), 3.11 (m, 2H), 2.94-2.81 (m, 3H), 2.30 (m, 2H), 2.09 (t, J=7.3 Hz, 2H), 1.92-0.94 (m, 35H), 0.90 (s, 3H), 0.87 (d, J=6.4 Hz, 3H), 0.84 (d, J=2.4 Hz, 3H), 0.83 (d, J=2.4 Hz, 3H), 0.60 (s, 3H); 13C NMR (125.8 MHz, DMSO d6) δ 172.7, 145.1, 144.4, 144.1, 138.5, 137.9 122.4 (×2), 99.0, 56.6, 56.0, 55.5, 49.3, 43.3, 41.8, 41.7, 41.6, 36.4, 36.1, 35.6, 35.4, 35.1 (×2), 34.3, 31.2 (×2), 27.7, 27.4, 26.3, 26.1, 24.9, 24.4, 23.8, 23.7, 23.1, 22.6, 22.4, 20.4, 18.7, 18.5 (×2), 11.6; IR (film) νmax 3269, 2949, 2868, 1649, 1585, 1530, 1300 cm−1; CI m/z 719.5224 (MH+, C42H67N6O4 requires 719.5224).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][CH2:15][CH:16]([C:19]([O:21]C)=[O:20])[CH2:17][CH2:18][C:12]=3[O:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH2:14][CH2:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][CH2:18][C:12]=3[O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCc2onc(-c3ccc(OC)cc3)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2noc3c2CCC(C(=O)O)CC3)cc1
Temperature: 20 °C
Reaction time: 66 h
Yield: 67.8 %

Procedure:
1.7 g (0.00565 mol) of methyl 5,6,7,8-tetrahydro-3-(4-methoxyphenyl)-4H-cyclohept[d]isoxazole-6-carboxylate were dissolved in 20 ml of methanol. 1 g of potassium hydroxide in 3 ml of water was added and the mixture was stirred at 20° C. for 66 hours. The methanol was removed by evaporation and an excess of water was added. The mixture was acidified with dilute hydrochloric acid and the resulting precipitate was filtered off, washed with water and dried. Crystallization from ethyl acetate/hexane gave 1.1 g of 5,6,7,8-tetrahydro-3-(4-methoxyphenyl)-4H-cyclohept[d]isoxazole-6-carboxylic acid of melting point 147°-148° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:22]#[N:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Heat a solution of 4-(5-bromo-3-methyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (5.0 g, 14.0 mmol), Zn(CN)2 (989 mg, 8.4 mmol) and Pd(PPh3)4 (970 mg, 0.84 mmol), in dry DMF (50 mL) at 80° C. for 16 h under nitrogen in a sealed tube. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the title compound, and use immediately for the next reaction.
Reaction SMILES: C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[C:16]#[N:17].[OH-].[Na+]>C(OCC)(=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH2:16][NH2:17]
Reactant: N#Cc1ccc(N2CCOCC2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCc1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a THF (30 mL) suspension of lithium aluminum hydride (975 mg), a THF (10 mL) solution of 3-fluoro-4-(morpholin-4-yl)benzonitrile (4.41 g) was added dropwise at −78° C. Then, the reaction solution was allowed to be warmed to room temperature and agitated overnight. The reaction solution was cooled to 0° C. after confirming disappearance of the starting materials, water and 5N sodium hydroxide solution, and also ethyl acetate were added to the reaction solution one by one, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: ethyl acetate=1:1->heptane-ethyl acetate), and 3.60 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:27]=[C:14]3[CH:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH2:25]O)[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1.CCN(S(F)(F)[F:40])CC.O.C(=O)(O)[O-].[Na+]>ClCCl>[F:40][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:15]1[CH2:16][CH2:17][CH2:18][N:13]2[N:12]=[C:11](/[CH:10]=[CH:9]/[C:7]3[CH:6]=[CH:5][C:4]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:3]([O:2][CH3:1])[N:8]=3)[N:27]=[C:14]12
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2CO)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2CF)ccc1-n1cnc(C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
{2-{2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}methanol (350 mg) was dissolved in dichloromethane (40 mL). This was added dropwise to a solution of DAST (1.04 mL) in dichloromethane (6 mL) cooled to −78° C., and the reaction solution was stirred for one hour. Saturated sodium bicarbonate water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (carrier: NH silica, elution solvent: ethyl acetate:methanol=9:1) to obtain a racemate of the title compound (70 mg). The resulting racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title optically active compound with a retention time of 7 minutes and positive optical rotation (20 mg) and the title optically active compound with a retention time of 9 minutes and negative optical rotation (20 mg), where the retention time is an analysis result in CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (Lot. IB00CD-FD026, mobile phase: ethanol, flow rate: 0.5 mL/min).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:25])([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br.[Br-].[K+].S([O-])([O-])=O.[Na+].[Na+].CBr>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([P:9](=[O:25])([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(P(=O)(c2ccc(C)cc2)c2ccc(OC)cc2)cc1
Agent: Br
Agent: CBr
Agent: O=S([O-])[O-]
Product: Cc1ccc(P(=O)(c2ccc(O)cc2)c2ccc(O)cc2)cc1
Temperature: 110 °C
Reaction time: 112 h
Yield: 67.9 %

Procedure:
A mixture of bis(4-methoxyphenyl)(4-methylphenyl)phosphine oxide mixture (470.2 g, 1.33 mol), hydrobromic acid (1458.1 g, 48%, 8.65 mol), and potassium bromide (45.0 g, 0.378 mol) were stirred for 112 h at 110° C. The flask was fitted with a sodium sulfite scrubber for containment of methyl bromide. The lower aqueous layer was removed and the molten product layer was worked up to give bis(4-hydroxyphenyl)-(4-methylphenyl)phosphine oxide mixture as a tan powder (292.8 g, 77% yield). m.p. (DSC): 142.5° C. 31P NMR (d6-DMSO): 28.33 (s, 90.1%), 28.14 (s, 9.86%). LC (area %, THF:MeCN:water, 5:15:30): 16.2, 48.9, 20.1.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Br:11][CH2:12][C:13](Br)=[O:14]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:11][CH2:12][C:13]([NH:1][CH2:2][C@@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:14]
Reactant: O=C(Br)CBr
Reactant: NC[C@@H](O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CBr)NC[C@@H](O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) biphasic solution of (S)-(+)-2-amino-1-phenylethanol (6.2 g, 45.2 mmol) in EtOAc (450 mL) and saturated aqueous NaHCO3 (125 mL) was added bromoacetyl bromide (4.32 mL, 49.7 mmol) via syringe. The mixture was stirred at 0° C. for 1 h then layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL) then combined organics were dried with Na2SO4, filtered, and concentrated to dryness to afford the desired product as a residue (11.6 g, quant.) that was used in the next transformation: ES MS (+) m/z 258.
Reaction SMILES: [N+](=C)=[N-].[C:4]([C:7]([Cl:27])([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:6])[CH3:5].[C:28](O)(=O)C>CCOCC>[C:4]([C:7]([Cl:27])([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:28])=[O:15])(=[O:6])[CH3:5]
Reactant: CC(=O)O
Reactant: CCCCCC(O)CCCC(Cl)(CCCCCCC(=O)O)C(C)=O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCC(O)CCCC(Cl)(CCCCCCC(=O)OC)C(C)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in either (100 ml.) is mixed with a solution of 8-acetyl-8-chloro-12-hydroxyheptadecanoic acid (10.9 g., 0.03 mole) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 8-acetyl-8-chloro-12-hydroxyheptadecanoate, a colorless viscous oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[C:6]=2[N:22]=1.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=2)=[O:33])[CH2:28][CH2:27]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:38]3[CH:39]=[C:34]([C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][OH:23])[CH2:31][CH2:30]4)=[O:33])[CH:35]=[CH:36][CH:37]=3)=[N:22][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl
Reactant: O=C(c1cccc(B(O)O)c1)N1CCN(CCO)CC1
Product: O=C(c1cccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCCN3)c1)N1CCN(CCO)CC1

Procedure:
The entitled compound can be prepared from 2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine and 3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)phenylboronic acid as described in example 1 or 30.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[C:16]2[C:17](=[O:30])[N:18]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:19][CH2:20][CH2:21][C:15]=2[NH:14][CH:13]=1>ClCCl>[CH3:11][C:12]1[C:16]2[C:17](=[O:30])[N:18]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:19][CH2:20][CH2:21][C:15]=2[NH:14][C:13]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
Dichloromethane (36 ml, 559 mmol) and N,N-dimethylformamide (1.637 ml, 20.9 mmol) were stirred for 5 minutes at −15° C. in an ice-salt bath under an argon atmosphere. The solution was added dropwise with phosphorus oxychloride (1.07 ml, 11.5 mmol) and stirred for 15 minutes while maintaining the temperature at −10° C. 3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-on e 32c (1.26 g, 4.58 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above solution. Upon completion of the addition, the ice-salt bath was removed, and the reaction mixture was stirred for 3 hours at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with iced water, adjusted to about pH 10 with sodium hydroxide solution (10 mol/L) and stirred for 30 minutes, extracted with dichloromethane (30 ml×3). The combined organic extracts were washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (993 mg, yield 71.4%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)=[CH:6][C:4]=1[NH2:5].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:5][C:4]1[CH:6]=[C:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: COc1ccc(-c2cc(C)ccn2)cc1N
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(C)ccn2)cc1N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
To a suspension of 2-methoxy-5-(4-methylpyridin-2-yl)aniline (294 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (455 mg) and diisopropylethylamine (0.55 ml) in dichloromethane (15 ml) was added 1-methyl-2-chloropyridinium iodide (455 mg), and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 70 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(2-methoxy-5-(4-methylpyridin-2-yl)phenyl)guanidine (334 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:14]1[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]1.O.NN>CO>[CH3:22][CH:20]([N:17]1[CH2:18][CH2:19][N:14]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([NH2:9])=[C:6]([O:12][CH3:13])[CH:5]=2)[CH2:15][CH2:16]1)[CH3:21]
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1N1CCN(C(C)C)CC1
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(N2CCN(C(C)C)CC2)c(OC)cc1N
Yield: 63.5 %

Procedure:
A solution of 1-[2,5-bis(methyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazine (3.50 g, 11.3 mmol), FeCl3 (0.550 g, 3.4 mmol), activated carbon (4.0 g), and hydrazine hydrate (3.6 mL, 113 mmol) was heated in methanol (50 mL) for 3 hours. The mixture was filtered over celite and concentrated to give 4-[4-(1-methylethyl)-1-piperazinyl]-2,5-bis(methyloxy)aniline as a grey solid (2.00 g, 7.17 mmol, 63% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.10 (d, J=6.60 Hz, 6 H), 2.72 (s, 5 H), 3.03 (s, 4H), 3.59 (s, 2 H), 3.78 (s, 3 H), 3.79 (s, 3 H), 6.34 (s, 1 H), 6.57 (s, 1 H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:11][C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1.[CH:19]1(CBr)[CH2:21][CH2:20]1>>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH2:11][C:12]2([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]2)[CH2:21][CH2:20]1
Reactant: COCC1(S(N)(=O)=O)CC1
Reactant: BrCC1CC1
Agent: CC(C)(C)NC(=O)O
Product: NS(=O)(=O)C1(CC2CC2)CC1
Yield: 92 %

Procedure:
This compound was obtained in 92% yield according to the procedure described in the synthesis of 1-methoxymethylcyclopropylsulfonylamine tert-butylcarbamate (Step B.1.a) except 1.10 equivalents of cyclopropylmethyl bromide were used as electrophile. The compound was taken directly into the next reaction without purification: 1H NMR (CDCl3) δ 0.10 (m, 2H), 0.51 (m, 2H), 0.67 (m, 1H), 1.10 (m, 2H), 1.49 (s, 9H), 1.62 (m, 2H), 1.87 (d, J=7.0 Hz, 2H).