Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[S:22])[NH2:21])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20](=[S:22])[NH2:21]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=S)[C@H](N)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
((1R)-2-(2-Naphthyl)-1-thiocarbamoylethyl)carbamic acid tert-butylester (0.45 g; 1.36 mmol) was dissolved in methylene chloride (1.5 ml) and trifluoroacetic acid (1.5 ml) was added. The reaction mixture was stirred for 40 min at room temperature. The solvent was removed in vacuo and the residue was dissolved in methylene chloride. Aqueous sodium hydrogencarbonate was added until basic reaction and the aqueous phase was extracted with methylene chloride (3×15 ml). The combined organic phases were dried (MgSO4) and the solvent was removed in vacuo to afford 0.311 g of (2R)-2-amino-3-(2-naphthyl)propionthioamide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:10]=1Br.[Li]CCCC.CN(CCN(C)C)C.[CH:37]1[CH:42]=[C:41]([CH:43]=[O:44])[N:40]=[CH:39][CH:38]=1>CCOCC>[N:40]1[CH:39]=[CH:38][CH:37]=[CH:42][C:41]=1[CH:43]([C:10]1[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[OH:44]
Reactant: Brc1c(COC2CCCCO2)cccc1COC1CCCCO1
Reactant: O=Cc1ccccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccccn1)c1c(COC2CCCCO2)cccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
To a solution of 2,6-di(tetrahydro-2H-2-pyranyloxymethyl)-phenyl bromide (15.5 g, 39 mmol) in ether at -30° C. was added n-BuLi (2.5M, 16.4 ml, 41 mmol) and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was cooled to 0° C., and TMEDA (4.56 g, 37 mmol) was added, and the resulting mixture was cooled to -50° C. After stirring for 20 minutes, 2-pyridylcarboxaldehyde (6.31 g , 58 mmol) was added. The above mixture was warmed to room temperature over a period of 2 hours, quenched with saturated sodium bicarbonate, and diluted with ethyl acetate with stirring. The organic layer was washed with brine and concentrated in vacuo to afford 11.7 g (73%) of 1-(2-pyridyl)-1-[2,6-di(tetrahydro-2H-2-pyranyloxymethyl)phenyl]-methanol as an oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1([CH3:16])[NH:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]([O-:15])=[O:14].[Na+].[CH2:18](O)[CH3:19]>>[CH3:5][C:6]1([CH3:16])[NH:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]([O:15][CH2:18][CH3:19])=[O:14]
Reactant: CCO
Reactant: CC1(C)NCC(=O)N1CC(=O)[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN1C(=O)CNC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(1) To an ice cold solution of thionyl chloride (5 ml) in dry ethanol (50 ml) a solution of sodium 2,2-dimethyl-5-oxo-1-imidazolidineacetate (4 g) in dry ethanol (50 ml) was added dropwise. The mixture was stirred at 0° C. for 1 hour, then at room temperature overnight. After evaporation under reduced pressure, the residue was taken up with a saturated solution of sodium hydrogen carbonate and extracted with 3×100 ml of dichloromethane. The organic layer was dried and evaporated, to yield ethyl 2,2-dimethyl-5-oxo-1-imidazolidineacetate (2.57 g) as a colorless oil (Rf. 0.49, methanol/acetone 1:1; silica gel plates). Oxalate salt m.p. 109°-113° C. (ethanol/diethyl ether).
Reaction SMILES: Br[C:2]1[C:3]([C:20]#[N:21])=[N:4][C:5]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:7]=1.[OH:22][CH:23]1[CH2:27][CH2:26][O:25][CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH:17]1([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([C:5]3[N:4]=[C:3]([C:20]#[N:21])[C:2]([O:22][CH:23]4[CH2:27][CH2:26][O:25][CH2:24]4)=[CH:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)[CH2:19][CH2:18]1
Reactant: OC1CCOC1
Reactant: N#Cc1nc(C(=O)N2CCCN(C3CC3)CC2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1nc(C(=O)N2CCCN(C3CC3)CC2)ccc1OC1CCOC1
Temperature: 150 °C
Yield: 45.9 %

Procedure:
A mixture of 3-bromo-6-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-pyridine-2-carbonitrile (0.600 g, 1.71 mmol), 3-hydroxytetrahydrofuran (301 mg, 3.41 mmol), and anhydrous Cs2CO3 (1.67 g, 5.13 mmol) in DMSO (7 mL) was heated by microwave irradiation at 150° C. for 35 min. The mixture was diluted with water and extracted with Et2O. The combined organic layers were dried (Na2CO3) and concentrated. The residue was purified by FCC to give the title compound (280 mg, 46%). MS (ESI): mass calcd. for C19H24N4O3, 356.4; m/z found, 357.5 [M+H]+. 1H NMR (CDCl3): 7.94 (d, J=8.8 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 5.08-5.04 (m, 1H), 4.12-3.93 (m, 4H), 3.77-3.72 (m, 2H), 3.69-3.63 (m, 2H), 2.98-2.92 (m, 2H), 2.87-2.81 (m, 2H), 2.35-2.25 (m, 1H), 2.25-2.18 (m, 1H), 1.97-1.83 (m, 3H), 0.51-0.35 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH:8](C(=O)C)[CH2:7][CH:6](C(=O)C)[CH:5]1[C:15]#[N:16].ClC1C=CC=[C:20]([C:24]([O:26]O)=[O:25])C=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH:4]1[CH:8]([O:26][C:24](=[O:25])[CH3:20])[CH2:7][CH:6]([O:26][C:24](=[O:25])[CH3:20])[CH:5]1[C:15]#[N:16]
Reactant: CC(=O)C1CC(C(C)=O)C(CCCl)C1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CC(OC(C)=O)C(CCCl)C1C#N
Temperature: 50 °C
Yield: 76.8 %

Procedure:
A mixture of 0.46 g of 2-(2'-chloroethyl)-3,5-diacetyl-cyclopentanecarbonitrile, 2.05 g of meta-chloroperbenzoic acid and 15 ml of chloroform was heated at 50°C for 4 days. The reaction mixture was treated by the same procedure as set forth in Example 32 to afford 0.40 g of 2-(2'-chloroethyl)-3,5-diacetoxy-cyclopentanecarbonitrile as an oily substance. The product had the following characteristics: Infrared absorption (film method): 2250, 1740, 1430, 1370, 1230, 1045, 1020. Nuclear magnetic resonance (in CDCl3): about 5.3 (two multiplet, 2H, two methyne protons at the 3- and 5-position), 3.65 (triplet, J=7 cps, methylene protons adjacent to chlorine), 2.10 (two singlets, two acetoxy protons).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[C:6]1([S:5][CH2:4][CH2:3][CH2:2][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCSc1ccccc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(3-chloropropyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 382.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([O:9]C)=O)=[CH:5][N:6]=1.O.[NH3:12]>>[CH3:1][C:2]1[S:3][C:4]([C:7]([NH2:12])=[O:9])=[CH:5][N:6]=1
Reactant: N
Reactant: COC(=O)c1cnc(C)s1
Solvent: O
Product: Cc1ncc(C(N)=O)s1
Yield: 73 %

Procedure:
1.4 g Methyl 2-methylthiazol-5-carboxylate was added to 25 ml ammonia water, to carry out reaction at room temperature for 3 hr. The reaction product was cooled down, filtered, and washed with water to obtain 0.95 g a white powdery solid (73%) with mp 202-205 (C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1([C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
trans-4-(Methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g) obtained in Reference Example 1(2) is dissolved in chloroform (200 ml), and thereto are added pyrrolidine (9.2 g), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (24.7 g) and triethylamine (13.6 g) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed successively with 10% hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform, then chloroform/methanol=20/1) to give methyl trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxylate (11.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:9]=2[CH2:10]Cl)=[CH:4][C:3]=1[CH3:18].C([O:21][P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C>>[C:23]1([P:22]([CH2:10][C:9]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:18])[CH:4]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc(C)c(CCl)c(-c2ccc(F)c(C)c2)c1
Reactant: CCOP(c1ccccc1)c1ccccc1
Product: Cc1cc(C)c(CP(=O)(c2ccccc2)c2ccccc2)c(-c2ccc(F)c(C)c2)c1
Temperature: 150 °C

Procedure:
2.06 grams (7.84 mmol) of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzyl chloride was treated with ethyldiphenylphosphinite (2.08 grams, 9.01 mmol) and heated to 150° C. for 3 hrs. After cooling to room temperature, the crude mixture was purified by silicagel chromatography ((10% acetone/90% methylene chloride) and the appropriate fractions concentrated and recrystallized from ether/hexane to provide the title compound (MP 109-111° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Br:12]Br.Cl>CO.[OH-].[Na+]>[Br:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]nc(Br)c2c1
Temperature: 40 °C
Yield: 92 %

Procedure:
1H-Indazole-5-carbonitrile (5.3 g, 36.8 mmol) was dissolved in methanol (60 mL) and aqueous sodium hydroxide (30 mL). Bromine (7.07 g, 44.4 mmol) in solution in 2.0 N aqueous sodium hydroxide (30 mL) was added with a disposable pipet. The reaction mixture was then heated to 40° C. for 1.5 hours. The reaction was cooled to room temperature and acidified with 6.0 N aqueous hydrochloric acid. The resulting solid was collected by filtration and washed 3 times with 20-mL portions of water. The solid was dried under vacuum for 1 day. The solid was used without further purification. (7.54 g, 92% yield): 1H NMR (CDCl3) δ 13.3 (br s, 1H), 8.0 (s, 1H), 7.5 (s, 2H); ES-MS (m/z) 224 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Li]CCCC.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1
Reactant: Cc1cc(C)c2c(n1)N(C)CC2
Reactant: CCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1cc(C)c2c(n1)N(C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing −490 mg (2.71 mmol) of 1,4,6-Trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 7.2 mL of THF was added 2.70 mL (4.34 mmol) of n-BuLi (1.6 M in hexanes) followed by 4504 (509 mg, 2.85 mmol) of 1-bromoheptane at −78° C. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was quenched by the addition of 25 mL of sat aq. NH4Cl at 0° C. The mixture was extracted with three 40-mL portions, of EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The residue was purified via flash chromatography on a silica gel column (42×2.5 cm). Step gradient elution with 1:10→1:4 ethyl acetate-hexanes as eluent gave 1,4-dimethyl-6-octyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine as a yellow oil: yield 402 mg (57%); silica gel TLC Rf 0.36 (8:1:1 hexanes-ethyl acetate-methanol); 1H NMR (CDCl3) δ 0.79 (t, 2H, J=7.2 Hz), 1.16-1.30 (m, 10H), 1.58 (quint, 2H, J=8.0 Hz), 2.00 (s, 3H), 2.48 (t, 2H, J=8.0 Hz), 2.72 (t, 2H, J=8.4 Hz), 2.82 (s, 3H), 3.38 (t, 2H, J=8.4 Hz), 6.14 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH2:12][C:13]2[N:14]=[C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:16][CH:17]=2)=[CH:6][CH:5]=1.[O:27]([CH2:34][C@@H:35]1[CH2:37][O:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(O)C>[CH2:19]([NH:18][C:15]1[S:16][CH:17]=[C:13]([CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][CH2:37][C@H:35]([OH:36])[CH2:34][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:5][CH:6]=2)=[O:26])[N:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: NCCc1ccc(NC(=O)Cc2csc(NCc3ccccc3)n2)cc1
Solvent: CC(C)O
Product: O=C(Cc1csc(NCc2ccccc2)n1)Nc1ccc(CCNC[C@H](O)COc2ccccc2)cc1
Yield: 26.5 %

Procedure:
A solution of 670 mg of N-[4-(2-aminoethyl)phenyl]-2-(2-benzylaminothiazol-4-yl)acetamide and 300 mg of (S)-2-[(phenoxy)methyl]oxirane in 20 ml of 2-propanol was heated under refluxing for three hours. The solvent was evaporated off in vacuo and the residue was purified by means of silica gel column chromatography (eluate: chloroform/methanol=10/1). The resulting solid was recrystallized from methanol to obtain 250 mg of (S)-2-(2-benzylamino-4-thiazolyl)-4'-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethyl]acetanilide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9](=O)([O:20]C1C=CC([N+]([O-])=O)=CC=1)[O:10][C@@H:11]1[CH2:15][O:14][C@@H:13]2[C@H:16]([OH:19])[CH2:17][O:18][C@H:12]12>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:9](=[O:20])([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[O:10][C@@H:11]1[CH2:15][O:14][C@@H:13]2[C@H:16]([OH:19])[CH2:17][O:18][C@H:12]12
Reactant: OCCCCCCCl
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCCCCCCCl)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-nitrophenyl carbonate (1.13 g, 3.63 mmol) in DCM (15 ml), (prepared as described in EXAMPLE 7, Step C), 6-chlorohexanol (596 mg, 4.36 mmol) and 4-dimethylaminopyridine (89 mg, 0.73 mmol) were added and the mixture was stirred at room temperature for 18 hrs. Then the mixture was diluted with DCM and washed with a 5% solution of sodium dihydrogen phosphate (20 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 12 to 80%), affording the title compound as colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Cl)[CH:8]=1>>[CH3:1][N:2]([CH2:13][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: ClCc1cccnc1
Reactant: CNCCNC
Product: CNCCN(C)Cc1cccnc1
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To 7.50 gm of N,N'-dimethylethylenediamine which has been cooled in an ice-ethanol bath is added portionwise over a 30 minute period 1.40 gm of 3-picolyl chloride. After stirring cold for 1 hour after the addition is completed, the reaction mixture is concentrated in vacuo and the residue partitioned between 50 ml of ether and 10 ml of 5N NaOH solution. The organic layer is separated and the aqueous layer extracted 2 times with 50 ml of ether. The combined organic extracts are dried through sodium sulfate and concentrated in vacuo. Chromatography on 150 gm silica gel using CH2Cl2 /CH3OH/NH4OH (90/10/1) as eluent gives 0.930 g of N,N'-dimethyl-N-(3-pyridylmethyl)ethylenediamine.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([Cl:16])[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O.[NH2:24][NH2:25]>C(O)C>[Cl:16][C:6]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][N:3]=[C:2]2[NH:24][N:25]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=12
Reactant: O=C(c1ccccc1)c1c(Cl)nnc(-c2ccccc2)c1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Temperature: 40 °C
Reaction time: 1 h
Yield: 8.5 %

Procedure:
A mixture of (3,5-dichloro-6-phenylpyridazin-4-yl)(phenyl)methanone (150 mg, 0.46 mmol) and hydrazine hydrate (27 mg, 0.55 mmol) in ethanol (0.5 mL) was stirred at 40° C. for 1 h in a sealed tube. The reaction mixture was cooled and filtered, and the residue was washed with diethyl ether. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, gradient 0 to 20% ethyl acetate/isohexane) yielding Compound 9 as a white solid (12 mg).
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:11][CH2:10][C@@H:9]2[CH2:12][CH2:13][CH2:14][N:8]2[CH2:7]1)(=O)C.C[O-].[Na+].Cl.O1CCOCC1>ClCCl>[CH2:10]1[C@@H:9]2[CH2:12][CH2:13][CH2:14][N:8]2[CH2:7][C@@H:6]([CH2:5][OH:4])[O:11]1
Reactant: CC(=O)OC[C@@H]1CN2CCC[C@H]2CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: OC[C@@H]1CN2CCC[C@H]2CO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.2 %

Procedure:
(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate (2.36 g, 11.9 mmol) was treated with sodium methoxide (25 wt % solution in methanol; 2.7 mL) for 0.5 h. The mixture was cooled in an ice bath and a solution of 4M HCl in 1,4-dioxane (3 mL, 12.0 mmol) was added slowly. The mixture was stirred at room temperature for 5 minutes and then was concentrated in vacuo to afford a suspension which was diluted with dichloromethane, filtered and the filtrate was concentrated in vacuo to afford (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethanol as a brown oil (1.93 g, >100% yield). 1H NMR (400 MHz, CDCl3): 4.05 (dd, 1H), 3.73-3.65 (m, 2H), 3.62-3.56 (m, 1H), 3.39-3.34 (m, 1H), 3.10 (dt, 1H), 3.00-2.95 (m, 1H), 2.24-1.98 (m, 4H), 1.97-1.70 (m, 3H), 1.44-1.28 (m, 1H); MS (EI) for C8H15NO2: 158 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[N:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH:12]=[C:8]2[C:7](=[O:20])[NH:6][CH2:5]1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22].O>C(Cl)Cl>[CH3:24][S:21]([O:1][CH2:2][CH2:3][CH:4]1[N:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH:12]=[C:8]2[C:7](=[O:20])[NH:6][CH2:5]1)(=[O:23])=[O:22]
Reactant: O=C1NCC(CCO)n2cc(-c3cccc(Cl)c3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 4-(2-hydroxyethyl)-7-(3-chlorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (128 mg, 0.44 mmol) in DCM (10 ml), mesyl chloride (58 ul, 0.748 mmol) and TEA (200 ul, 1.48 mmol), were added. The resulting solution was stirred at room temperature, after 1 h the reaction mixture was portioned between DCM and water. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give 2-[1-oxo-7-(3-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]ethyl methanesulfonate as a solid 157 mg (97%).
Reaction SMILES: [CH:1]([NH:4][S:5](Cl)(=[O:7])=[O:6])([CH3:3])[CH3:2].[C:9]([NH:13][C:14](=[NH:19])[O:15][CH:16]([CH3:18])[CH3:17])([O:11][CH3:12])=[O:10].C(N(CC)CC)C>O1CCCC1>[C:9]([NH:13][C:14](=[N:19][S:5](=[O:7])(=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[O:15][CH:16]([CH3:17])[CH3:18])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)NC(=N)OC(C)C
Reactant: CC(C)NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NC(=NS(=O)(=O)NC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In the course of 25 minutes, 95 parts of isopropylaminosulfonyl chloride were stirred into a mixture of 96 parts of N-carbomethoxy-O-isopropylisourea and 73 parts of triethylamine in 700 parts of tetrahydrofuran at 10°-15° C. After then stirring for one hour at 25° C., the reaction mixture was extracted once with water and once with 0.5 N hydrochloric acid, dried and evaporated down under reduced pressure. This gave 130 parts of N-carbomethoxy-N'-isopropylsulfamyl-O-isopropyl-isourea, of melting point 62°-64° C. 33.7 parts of this product were cyclized with 17.6 parts of 50% strength by weight sodium hydroxide solution in 30 parts of water for 5 minutes at 55°-60° C. The mixture was extracted with ether and then acidified, and the product was filtered off, washed with water and dried, giving 22 parts of 6-isopropyl-3-isopropoxy-6H-1,2,4,6-thiatriazin-5-one,1,1-dioxide of melting point 164°-167° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][NH2:10]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][CH3:9])=[N:3][CH:4]=1
Reactant: CN
Reactant: Brc1ccc(Br)nc1
Solvent: CCO
Product: CNc1ccc(Br)cn1
Temperature: 80 °C

Procedure:
A 20 ml microwave reaction vessel is charged with 2,5-Dibromo-pyridine (2.00 g, 8.44 mmol) and treated with methylamine (10.45 ml of a 33% solution in ethanol, 84.43 mmol) and warmed to 80° C. for 3 days. After this time the reaction is concentrated and the remaining solid is treated with 1M HCl (50 ml) and DCM. The layers are separated and the aqueous phase is basified using 1N NaOH (to pH-11). The product was extracted into DCM (2×) and the combined organics were dried (MgSO4), filtered and concentrated to give the desired product I-96bis (1.20 g). 1H-NMR (400 MHz, DMSO-d6): 2.75 ppm (d, 3H), 6.44 ppm (d, 1H), 6.72 ppm (bs, 1H), 7.51 ppm (dd, 1H), 8.05 ppm (s, 1H)
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:25])[N:15]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[OH:9][CH:8]([C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:25])[N:15]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:16]3=[N:17]2)=[CH:12][CH:11]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)c1ccc2c(=O)n3c(nc2c1)CCCCC3
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1c2ccc(C(O)Cc3ccccc3)cc2nc2n1CCCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-phenylacetyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one, obtained from Example 21.3 (100 mg, 0.3 mmol) and excess NaBH4 in CHCl3/MeOH (10 mL, 1:1) was stirred at room temperature for 2 h. After quenching with water, the reaction solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were concentrated. The residue was purified by silica gel chromatography to give the desired product. MS (ESI): 335 (MH+); 1H NMR (300 MHz, CDCl3) δ: 8.18-8.16 (d, J=8.19 Hz, 1H), 7.82 (s, 1H), 7.41-7.28 (m, 6H), 5.05-5.01 (t, J=7.65 Hz, 1H), 4.49-4.46 (t, J=5.01 Hz, 2H), 3.76 (brs, 1H), 3.36-3.33 (t, J=4.08 Hz, 2H), 3.23-3.20 (m, 2H), 2.00-1.86 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[CH3:33][C:34]1[CH:41]=[CH:40][C:37](CO)=[CH:36][CH:35]=1>CC(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:37]2[CH:40]=[CH:41][C:34]([CH3:33])=[CH:35][CH:36]=2)[CH2:14][CH2:13]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reactant: Cc1ccc(CO)cc1
Solvent: CC(C)O
Product: Cc1ccc(COCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1

Procedure:
Compound 22 was prepared in a similar manner to compound 7, substituting the commercially available 4-methyl-benzylalcohol for 2-propanol in part C. MS (M+1)=426.41