Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([C:16]#[N:17])=[C:5]([Cl:18])[N+:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>CO>[Cl-:18].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([C:16]#[N:17])=[C:5]([NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[N+:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: CCCCCCNc1cc(N)[n+](CCCCCC)c(Cl)c1C#N
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCCCNc1cc(N)[n+](CCCCCC)c(NCCCC)c1C#N
Yield: 61 %

Procedure:
3.37 gms (.01 mole) of 2-amino-6-chloro-5-cyano-1-n-hexyl-4-n-hexylamino pyridinium chloride (compound II - Table 1) was dissolved in methanol and 1.0 gm (0.01 mole) of triethylamine and 0.8 gms (0.011 mole) of n-butylamine added. The solution was refluxed for 1 hour and on cooling 2.5 gms (60% yield) of 2-amino-6-n-butylamino-5-cyano-1-n-hexyl-4-n-hexylamino pyridinium chloride (compound 42 - Table 2) crystallised out. [m.p. 179° - 180°C. c 64.88 (64.6) H 9.81 (9.78) N17.11 (17.1)].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[C:12](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[CH3:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(F)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(F)cc1C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
4-Fluoro-2-methylbenzoic acid (1.6 g, 10.3 mmol) was dissolved in CH2Cl2 (20 mL) and DMF (1 drop) and stirred as oxalyl chloride (10.3 mL, 20.8 mmol) was added. The reaction stirred for 15 minutes before the solvent was removed under reduced pressure. The product was dissolved in anhydrous CH2Cl2 and MeOH (5 mL) and stirred for a further 15 minutes. The solvent was removed under reduced pressure and purified by column chromatography on silica (2% EtOAc/Hexanes) to afford a colourless oil (1.33 g). 1H NMR (300 MHz, CDCl3): δ 7.95 (d, 1H), 6.96 (d, 1H), 6.75-6.77 (m, 1H), 3.86 (d, 3H), 2.62 (d, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:23]([O:25][CH3:26])=[O:24].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 638.8 %

Procedure:
A solution of 4.00 g (2.00 mmol) of 4-amino-1-BOC-piperidine and 4.18 ml (3.00 mmol) of Et3N in 50 ml of CH2Cl2 was treated at 0° C. with 1.62 ml (2.10 mmol) of methyl chloroformate. The reaction was stirred for 16 h at RT, neutralized with aqueous 10% KHSO4 and extracted with CH2Cl2 (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n- heptane/EtOAc 1:1 to 1:2) to yield 3.30 g (64%) of the title compound as white solid. MS: 259.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:42][CH2:41][CH2:40][CH2:39]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:39][CH:40]4[CH2:42][CH2:41]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)ccc4F)cc3)c3c(N)ncnc32)C1
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)ccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.9 %

Procedure:
Into a 10 sealed tube, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 031 mmol, 1.00 equiv) in methanol (5 mL), piperidine (78 mg, 0.92 mmol, 3.0 equiv), and cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.0 equiv). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with dichloromethane and washed with saturated aqueous ammonium chloride, water and brine. The organics were dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 38 mg (23%) of 2-[[(3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]carbonyl]-3-cyclopropylprop-2-enenitrile as a white solid. LC-MS (ES, m/z): 542 [M+H], H-NMR (CDCl3, ppm): δ8.51 (s, 1H); δ7.66 (d, 2H); δ7.12 (m, 3H); δ6.88 (m, 2H); δ6.51 (d, 1H); δ5.57 (s, 2H); δ4.95 (m, 1H); δ4.82 (m, 1H); δ4.23 (m, 1H); δ3.65 (m, 1H); δ3.28 (m, 1H); δ2.33 (m, 2H); δ2.01 (m, 2H); δ1.83 (m, 1H); δ1.20 (m, 2H); δ0.78 (m, 2H).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([O:5][CH3:6])=[O:4].[SH:25][CH2:26][CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:2]([S:25][CH2:26][CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)[C:3]([O:5][CH3:6])=[O:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCc1ccccc1C(Cl)C(=O)OC
Reactant: SCCc1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCc1ccccc1C(SCCc1nnn[nH]1)C(=O)OC
Reaction time: 18 h

Procedure:
A mixture of methyl 2-chloro-2-(2-dodecyl phenyl)acetate (0.615 g, 1.75 mmol), 5-(2-mercaptoethyl)-tetrazole (0.227 g, 1.75 mmol), and triethylamine (0.48 ml), 3.5 mmol) in 20 ml of methylene chloride was stirred 18 hours at 22° and the solvent was evaporated. The residue taken up in diethyl ether, washed with 1 N hydrochloric acid, dried and the solvent removed. The residue was chromatographed over a silica gel column. Impurities were eluted with ethyl acetate/hexane (1:3), and the product was eluted with methanol/ethyl acetate (1:19). Evaporation of the solvents from these fractions gave the desired product, 0.570 g (73%).
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.C1(S(O)(=O)=O)C=CC=CC=1.[NH2:21][C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[C:34]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=2)([CH2:48][CH2:49][CH2:50]OS(C)(=O)=O)[CH2:43]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[NH2:21][C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:27][CH2:26][N:25]([CH2:50][CH2:49][CH2:48][C:44]2([C:56]3[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=3)[CH2:45][CH2:46][CH2:47][N:42]([C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:43]2)[CH2:24][CH2:23]1
Reactant: NC1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 100 °C
Yield: 59.2 %

Procedure:
A mixture of 6.81 g of 4-amino-4-phenylpiperidine dibenzenesulfonate, 5.2 g of the compound obtained in step B of EXAMPLE 1 and 6.1 g of K2CO3 in 30 ml of a DMF/acetonitrile mixture (50/50; v/v) is heated at 100° C. for 5 hours. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (from 99/1; v/v to 85/15; v/v) as the eluent to give 3.6 g of the expected product.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]=2[F:12])[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]=2[F:12])[CH:5]=[C:4]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:26]=2)[N:3]=1
Reactant: CCCCCCCCc1ccc2cc(-c3ccc(O)cc3)nc(F)c2c1F
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cc3ccc(CCCCCCCC)c(F)c3c(F)n2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1,8-difluoro-3-(4-hydroxyphenyl)-7-octylisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1 -octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1,8-difluoro-3-[4-(octyloxy)phenyl]-7-octylisoquinoline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[ClH:46].O1CCOCC1>C(Cl)Cl>[ClH:46].[ClH:46].[ClH:46].[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:29]=[CH:30][C:31]([C:34]3([NH2:38])[CH2:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4cccc([N+](=O)[O-])c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4cccc([N+](=O)[O-])c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
tert-Butyl (1-{4-[2-(3-nitrophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (30.0 mg, 0.0499 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 18 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (21.7 mg, 71.3%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.69 (br s, 2H), 8.64 (s, 1H), 8.23 (t, J=1.8 Hz, 1H), 8.14-8.08 (m, 2H), 8.00 (dd, J=8.0, 1.8 Hz, 1H), 7.93-7.88 (m, 1H), 7.64-7.57 (m, 3H), 7.44-7.36 (m, 3H), 7.34-7.29 (m, 1H), 7.18-7.12 (m, 1H), 6.98 (dd, J=8.0, 1.8 Hz, 1H), 6.75 (dd, J=8.0, 4.8 Hz, 1H), 2.65-2.46 (m, 4H), 2.26-2.12 (m, 1H), 1.93-1.78 (m, 1H); LCMS: 501 [M+H].
Reaction SMILES: [CH2:1]([N:4]([CH3:10])[C:5](=O)[N:6]([CH3:8])[CH3:7])[CH:2]=[CH2:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:4]([CH3:10])[C:5]([N:6]([CH3:8])[CH3:7])=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCN(C)C(=O)N(C)C
Reactant: Nc1ccccc1N1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: C=CCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-allyl-1,1,3-trimethylurea (7.17 g) in benzene (50 ml) with 4-(2-aminophenyl)morpholine (6 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.71 ml) for 45 hours at 70° C. gave 1-allyl-2-(2-morpholinophenyl)-1,3,3-trimethylguanidine (bp. 148°-150° C. at 0.2 mm Hg).
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>>[F:19][C:18]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[CH3:27])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)c1ccccn1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)c1ccccn1
Yield: 7 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 2-(pyridin-2-yl)but-3-yn-2-ol to give the titled compound as a white solid (18 mg, 7%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][NH:3]1)=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=3[Cl:18].[OH-:19].[K+].Cl>C(O)C.O>[NH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[C:10]([Cl:18])[C:11]([Cl:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[C:2]([OH:19])=[O:1]
Reactant: COc1cc2c3c([nH]c2c(Cl)c1Cl)C(=O)NCC3
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc2c(CCN)c(C(=O)O)[nH]c2c(Cl)c1Cl
Yield: 96.9 %

Procedure:
The above lactam was hydrolyzed with base according to the following procedure: 5 g of 1-oxo-6-methoxy-7,8-dichloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole were dissolved in a mixture of 77 ml of ethanol and 51 ml of water. 13.9 g of potassium hydroxide were added, and the solution was heated to refluxing temperature overnight under a nitrogen atmosphere. The reaction mixture was cooled, and the pH adjusted to about 4 by the addition of 12N aqueous hydrochloric acid. A precipitate formed in the acidic solution, which precipitate was isolated by filtration, and the filter cake washed with water. 5.15 g of 3-(2-aminoethyl)-5-methoxy-6,7-dichloroindol-2-carboxylic acid were obtained. The compound melted at 248°-249° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][NH:11][CH2:12][CH2:13]CC#CC1C=CC(NC(=O)C(F)(F)F)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrCC[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([NH:52][CH2:53][C:54]1[C:55]([NH:67][CH:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)=[C:56]2[CH:64]=[N:63][N:62]([CH2:65][CH3:66])[C:57]2=[N:58][C:59]=1[CH2:60][CH3:61])=[O:51]>>[Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([NH:52][CH2:53][C:54]1[C:55]([NH:67][CH:68]2[CH2:69][CH2:70][O:71][CH2:72][CH2:73]2)=[C:56]2[CH:64]=[N:63][N:62]([CH2:65][CH3:66])[C:57]2=[N:58][C:59]=1[CH2:60][CH3:61])=[O:51])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCCCCCBr
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was prepared in a manner analogous to that described for Intermediate 37, using Intermediate 33 in place of Intermediate 26. ES/MS calcd. for C41H64N7O5Si 762.5. found m/z=762.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH:11]([CH3:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O)=[O:6])[CH:2]=[CH2:3].[N:16]1(O)[C:20]2[CH:21]=CC=C[C:19]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N)(C)C>ClCCl>[CH:20]([NH:16][C:13]([C@H:8]1[CH2:9][CH2:10][CH:11]([CH3:12])[N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[O:15])([CH3:21])[CH3:19]
Reactant: On1nnc2ccccc21
Reactant: C=CCOC(=O)N1C(C)CC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(C)N
Solvent: ClCCl
Product: C=CCOC(=O)N1C(C)CC[C@@H]1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-(Allyloxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (0.92 g, 4.3 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.70 g, 5.2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol), and isopropylamine (0.44 mL, 5.2 mmol) were dissolved in dichloromethane (2 mL) and stirred at ambient temperature for 16 h. The reaction was diluted with dichloromethane (100 mL), washed 3× with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 255(M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCc1ccccc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1cccc(OCCc2ccccc2)c1

Procedure:
3-Hydroxybenzamide (500 mg; 3.6 mM) was dissolved in dry acetonitrile (36 ml), and to this was added potassium carbonate (0.503 g; 3.6 mmol) and 2-(bromoethyl)benzene (0.498 ml; 3.6 mmol). The mixture was heated under reflux for two days. The acetonitrile was removed under reduced pressure to yield a white solid. This was dissolved in water and extracted into dichloromethane (3×30 ml). The organics were pooled, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure to yield a white solid. This was recrystallised from boiling ethyl acetate and petrol (0.459 g; 12.51%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C@@H:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[C:20]=3[CH3:28])[CH2:15][C:16](=O)[CH2:17][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C@@H:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[C:20]=3[CH3:28])[CH2:15][CH2:16][CH2:17][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([C@H]2CC(=O)C[C@H]3CN(Cc4ccccc4)CCN32)c(C)c1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc([C@H]2CCC[C@H]3CN(Cc4ccccc4)CCN32)c(C)c1C
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
(6R,9aS)-2-benzyl-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one (9.48 g, 25.0 mmol) is stirred with p-toluenesulfonyl hydrazide (5.60 g, 30.0 mmol, 1.2 eq) in 40 mL anhydrous THF and 200 mL anhydrous MeOH for 20 h at ambient temperature under a nitrogen atmosphere. LC/MS analysis indicates complete conversion to the p-toluenesulfonyl hydrazone. The solution is sparged with argon for 30 min and then treated with 50 mL of a 1.5 M solution of NaCNBH3 in MeOH. Zinc trifluoromethanesulfonate (140 mg, 0.376 mmoles, 1.5%) is added and the solution is heated in a 65° C. oil bath for 5.5 h under an argon balloon. LC/MS analysis indicates consumption of the hydrazone. The mixture is allowed to cool and is quenched with 500 mL of saturated NaHCO3. After stirring vigorously for 30 min, the mixture is extracted with CH2Cl2 (4×200 mL). The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with 90%-80% hexanes/EtOAc to yield (6R,9aS)-2-Benzyl-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazine as an oil. LC/MS: 365 (M+1). 1H NMR (400 MHz, CDCl3): 7.34 (1H, d), 7.27 (5H, m), 6.72 (1H, d), 3.79 (3H, s), 3.47 (2H, dd), 3.28 (1H, d), 2.68 (3H, m), 2.28-2.04 (8H, bm), 1.98-1.88 (2H, bm), 1.75 (1H, m), 1.59 (1H, d), 1.50-1.30 (4H, bm).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]=1[S:36](=[O:39])(=[O:38])[NH2:37]>O.O1CCOCC1>[C:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[C:28]([S:36](=[O:38])(=[O:39])[NH2:37])[CH:29]=2)[NH2:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: NNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NN(C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 56.4 %

Procedure:
By using the process of Example 1(B), 28 g of 4-benzoyl-2-nitrophenylhydrazine, 272 ml of dioxane, 5.8 g of anhydrous sodium carbonate dissolved in 110 ml of water and 27.6 g of 4-chloro-3-sulfamoylbenzoyl chloride dissolved in 217 ml of dioxane were used as starting materials to yield 29.1 g (61%) of 4-benzoyl-2-nitro-N-(4'-chloro-3'-sulfamoylbenzoyl)phenylhydrazine, m.p.: 148° C. after recrystallization from methanol.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH2:13])=[CH:3]1.[CH2:14]([N:21]([CH3:43])[C:22](=[O:42])[C@@H:23]([N:31]([CH2:39][CH:40]=O)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]([CH3:43])[C:22](=[O:42])[C@@H:23]([N:31]([CH2:39][CH2:40][NH:13][CH2:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][CH:3]=1)[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CC=O)C(=O)OC(C)(C)C
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CCNCCc1c[nH]c2ccccc12)C(=O)OC(C)(C)C

Procedure:
Prepare by the method of Example 1 using 2-(1H-indol-3-yl)-ethylamine hydrochloride salt (tryptamine hydrochloride salt) (0.197 g, 1.0 mmol) and (S)-N-benzyl-N-methyl-2-[N-(t-butoxycarbonyl)-2-oxo-ethylamino]-3-phenyl-propionamide (0.41 g, 1.0 mmol) to give the title compound: TLC Rf =0.69 (silica gel, 85% chloroform/10% methanol/5% acetic acid).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]([O:13][C:14]([NH:16][C:17]([CH3:22])([C:19](O)=[O:20])[CH3:18])=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C)CCCN=C=NCC>ClCCl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19](=[O:20])[C:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])([CH3:22])[CH3:18]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)ON1C(=O)CCC1=O

Procedure:
A stirred solution of N-hydroxysuccinimide (112 g, 0.973 mol), N-t-butoxycarbonyl-α-methylalanine (197 g, 0.969 mol), and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (186 g, 0.970 mol) in anhydrous dichloromethane (1.4 L) was stirred at room temperature for about 18 hours under nitrogen atmosphere. The reaction mixture was washed three times each with saturated sodium bicarbonate solution and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound of part 1-D as a white solid (256 g, 88%): PBMS (M+18)+ 318; 1H NMR=250 MHz (CDCl3) δ: 4.91 (NH, br, s, 1H), 2,84 (—CO(CH2)2CO—, s, 4H), 1.67 (Me, s, 6H), 1.48 (BOC, s, 9H).