Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([N:36]=[C:37](SC)SC)=[N:33][C:32]=2[CH:42]=1>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([NH:36][C:37]3[O:11][C@:3]4([CH2:2][N:1]=3)[CH:8]3[CH2:7][CH2:6][N:5]([CH2:10][CH2:9]3)[CH2:4]4)=[N:33][C:32]=2[CH:42]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1nc2cc(Cl)ccc2o1)SC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1ccc2oc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A 10 ml vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HCl salt (106 mg, 0.550 mmol), DMF (2 ml), DIEA (0.096 mL, 0.550 mmol), and Cs2CO3(358 mg, 1.100 mmol) at room temperature, followed by dimethyl 5-chlorobenzo[d]oxazol-2-ylcarbonimidodithioate (150 mg, 0.550 mmol). The resulting suspension was stirred at room temperature for 1 hr. LC/MS then indicated consumption of starting material. The reaction mixture was diluted with MeOH and purified by preparative HPLC to afford the expected product, (R)—N-(5-chlorobenzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (106.5 mg, 0.3 mmol, 53.0% yield), as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 2.08-2.30 (m, 3H) 2.35-2.48 (m, 1H) 2.60-2.73 (m, 1H) 3.48 (qd, J=7.53, 7.28 Hz, 3H) 3.54-3.68 (m, 1H) 3.79-4.00 (m, 2H) 4.18 (d, J=10.54 Hz, 1H) 4.35 (d, J=10.54 Hz, 1H) 7.19 (dd, J=8.53, 2.01 Hz, 1H) 7.30-7.47 (m, 2H) 9.10 (br. s., 1H). MS(LC/MS) R.T.=1.56; [M+H]+=333.13.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>CC(C)=O>[O:16]=[C:5]1[C:4]2[CH:3]=[C:2]([O:1][C:26](=[O:27])[CH2:25][CH2:24][Cl:23])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=C(Cl)CCCl
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(CCCl)Oc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 25 °C

Procedure:
5 g (22 mmol) of 2-hydroxy-9H-thioxanthen-9-one was dissolved in 200 ml refluxing acetone. 3.6 ml (3.5 g, 44 mmol) pyridine was added, followed by the addition of 5.6 g (44 mmol) 3-chloropropionyl chloride. The mixture was refluxed for 5 hours. The solvent was removed under reduced pressure, after cooling down to room temperature and the residue was dissolved in 200 ml methylene chloride. The methylene chloride was extracted with 150 ml of a 1 M Na2CO3 solution and 150 ml of a 0.1 N hydrochloric acid solution. The organic fraction was dried over MgSO4 and evaporated under reduced pressure. 3-chloro-propionic acid 9-oxo-9H-thioxanthen-2-yl ester was isolated by preparative column chromatography on a SVP D40 Merck NP column, using a gradient elution from methylene chloride (20 minutes isocratic elution) to methylene chloride/ethyl acetate 80/20 over 30 minutes and a flow rate of 50 ml/min. 0.414 g of 3-chloro-propionic acid 9-oxo-9H-thioxanthen-2-yl ester (6%) was isolated as a white crystalline compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]>>[CH2:18]([C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:35][C:32]3[CH:31]=[CH:30][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[CH:34][CH:33]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NN=C(Cc2ccccc2)/C1=C1\C=C(Cl)c2ccccc2N1
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3Cc3ccccc3)Nc3ccccc32)cc1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-benzyl-1H-pyrazol-5(4H)-one and 4-actamidothiophenol using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.94 (s, 2H) 2.11 (s, 3H) 6.77 (s, 1H) 7.23-7.32 (m, 3H) 7.42-7.50 (m, 2H) 7.65-7.69 (m, 3H) 7.83-7.93 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H); ESI-MS: m/z calc'd for C27H22N4O2S 466.15. found 467.4 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.Cl>C(O)(=O)C>[Br:2][C:3]1[C:4]2[NH:9][C:15]3[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][C:14]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccccc1Br
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCc2[nH]c3c(Br)cccc3c2C1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of (2-bromophenyl)hydrazine hydrochloride (1.1 g, 4.92 mmol; Aldrich) and 1-methyl-4-piperidone (0.56 g, 4.92 mmol; Aldrich) was combined with a solution of HCl in acetic acid (1.0 M, 30 mL; Aldrich) and stirred at 70° C. for 18 hours in a sealed tube. The reaction mixture was concentrated under vacuum. The residue was taken up in toluene (100 mL) and concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure was repeated a second time). The residue was dissolved in dimethyl sulfoxide (20 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.54 (s, 3H), 2.85-2.90 (m, 2H), 2.93-2.98 (m, 2H), 3.66 (t, J=1.5 Hz, 2H), 6.88 (t, J=7.8 Hz, 1H), 7.19 (dd, J=7.8, 0.8 Hz, 1H), 7.32 (dd, J=7.8, 0.8 Hz, 1H); MS (DCI) m/z 265/267 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[CH3:28][O:29][C:30]1[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl.C(N(CC)CC)C>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:2]
Reactant: COc1ccccc1N
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1cccc([C@H](C)Nc2nccc(-n3cnc4ccccc43)n2)c1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 58, 23.0 mg) and o-anisidine (22 μL, 0.20 mmol) were mixed in CH2Cl2 (2 mL) under nitrogen. Triethylamine (45 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38.5 mg) and dimethylaminopyridine (approx. 1 mg) were added and the mixture stirred at room temperature. After 19 h the mixture was concentrated in vacuo then eluted directly on silica gel (2:1 hexanes:acetone to 1:1 hexanes:acetone) to yield 9.1 mg of the title compound. Mass spectrum (ESI) 465.2 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].COC(C1ON=C(OC[C:35]2[C:36]([C:41]3C=CC=CN=3)=[N:37]OC=2C)C=1)=O.C(N)(C)C>>[CH:36]([NH:37][C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])([CH3:41])[CH3:35]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)ns1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Solvent: CC(C)N
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC(C)C)sn1
Yield: 83 %

Procedure:
As described for example 14e, 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol), instead of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester, was converted, using isopropyl amine (22 mg, 0.37 mmol), to the title compound (95 mg, 83%) which was obtained as an off white solid after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:4). MS: m/e=343.2 [M+H]+.
Reaction SMILES: CO[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:7]2[CH2:6]1.[NH2:17][CH2:18]CC#N>>[N+:14]([C:12]1[CH:13]=[C:7]2[CH2:6][N:5]([CH2:4][CH2:3][C:18]#[N:17])[CH2:10][CH2:9][N:8]2[N:11]=1)([O-:16])=[O:15]
Reactant: N#CCCN
Reactant: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Product: N#CCCN1CCn2nc([N+](=O)[O-])cc2C1
Yield: 81.4 %

Procedure:
Following the procedure of Example 296d, and starting with 1-(2-bromoethyl)-5-(chloromethyl)-3-nitro-1H-pyrazole 296d (268 mg, 1.00 mmol) and 3-aminopropanenitrile (210 mg, 3.00 mmol) afforded 338a as a white solid (180 mg, 81%). MS-ESI: [M+H]+ 222.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:12][C:13](=[O:19])[NH:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C@H:8]([CH3:11])[CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:7]1[CH2:12][C:13](=[O:19])[N:14]([CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:9][C@H:8]1[CH3:11])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCNC(=O)CN(C(=O)OC(C)(C)C)[C@H](C)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCN1C[C@@H](C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 60 °C
Yield: 62.8 %

Procedure:
A solution of but-3-enylcarbamoylmethyl-((R)-2-hydroxy-1-methyl ethyl)-carbamic acid tert-butyl ester (4.26 g, 14.9 mmol) in tetrahydrofuran (200 ml) was added dropwise at <10° C. to a mixture of triphenylphosphine (5.07 g, 19.3 mmol) and diisopropyl azodicarboxylate (3.91 g, 19.3 mmol), then the reaction mixture was heated at 60° C. for 2 h. After cooling and evaporation of volatile material, the residue was chromatographed (SiO2; heptane-ethyl acetate gradient) to afford the title compound (2.51 g, 63%). Yellow oil, MS (ISP)=269.3 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([OH:15])[C:10]([CH3:18])([CH2:16][CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH3:18][C:10]1([CH2:16][CH3:17])[CH:11]([OH:15])[CH:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: CCC1(C)CN(Cc2ccccc2)CC(C)C1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCC(C)C1O

Procedure:
A mixture of 1-benzyl-3,5-dimethyl-3-ethyl-4-hydroxypiperidine (2.9 g, 11.74 mmole) and 20% palladium hydroxide (0.5 g) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) for 8 hr at 35° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,5-dimethyl-3-ethyl-4-hydroxypiperidine as oil. Yield 1.7 g (93%), C9H19NO, m/z 158 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:5]1([CH:4]([C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[NH:1][CH:26]2[CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24][CH2:25]2)[OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1C(O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
2-Aminobenzhydrol from Step 1 above (1.0 g, 5 mmol), N-Boc-4-piperidone (2.0 g, 10 mmol), and acetic acid (0.86 mL, 0.9 g, 15 mmol) were combined in methanol (10 mL). Sodium cyanoborohydride (0.79 g, 12.5 mmol) was added in portions, and the mixture was stirred at ambient temperature for 42 hours. The mixture was concentrated in vacuo. Ethyl acetate (100 mL) was added to the residue and the resulting mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel eluted with 1:9 then 15:85 EtOAc:hexane. The combined product fractions were evaporated to dryness in vacuo to give phenyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[C:21]1[O:25][CH:24]=[N:23][CH:22]=1)[NH2:17]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Product: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)ccc1-c1cnco1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (600 mg, 2.84 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (5 ml) and TEA (395 μl, 2.83 mmol) was added. To this solution, 3-methoxy-4-(oxazol-5-yl)aniline (540 mg, 2.84 mmol, prepared according to S. H. Watterson et al. Bio. Med. Chem. Lett. 12 (2002) 2879-2882) in 5 ml DCM was dropwise added and the mixture was stirred for 30 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude (844 mg, 87% purity, 71% yield) was used in the next synthetic step without further purification.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][C:21](=[CH:23][C:24]#[N:25])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:38]=[CH:39][C:32]=23)[CH:28]=[N:27]1.C(#N)C.N12CCCN=C1CCCCC2>>[Si:1]([O:18][CH:19]1[CH2:22][C:21]([CH2:23][C:24]#[N:25])([N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]4[N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:38]=[CH:39][C:32]=34)[CH:28]=[N:27]2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (3-{[tert-butyl(diphenyl)silyl]oxy}cyclobutylidene)acetonitrile (4.0 g, 8.7 mmol, from Step 4 of Example 1a) and 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.50 g, 4.77 mmol, US 20090181959) in acetonitrile (10 mL, 200 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.68 mL, 4.6 mmol). The reaction was stirred overnight. A further portion of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.7 mL, 5 mmol) was added and the reaction was allowed to continue for an additional 72 hours. Acetonitrile was removed in vacuo. Flash chromatography on silica gel, eluting with 0%-30% EtOAc/Hexanes, was used to purify product, which was obtained as a mixture of diastereomers (2 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.33 (d, J=5.0 Hz, 1H major), 8.29 (d, J=5.0 Hz, 1H minor), 8.06 (s, 1H major), 8.03 (s, 1H major), 8.00 (s, 1H minor), 7.93 (s, 1H minor), 7.70-7.31 (m, 10H major and 10H minor), 7.19 (d, J=5.0 Hz, 1H major), 7.11 (d, J=5.0 Hz, 1H minor), 6.74 (d, J=3.6 Hz, 1H major), 6.63 (d, J=3.7 Hz, 1H minor), 5.71 (s, 2H major), 5.69 (s, 2H minor), 4.49-4.39 (m, 1H minor), 4.33 (tt, J=7.0, 7.0 Hz, 1H major), 3.67-3.45 (m, 2H major and 2H minor), 3.22 (s, 2H minor), 3.11-2.95 (m, 2H minor), 2.92-2.77 (m, 6H major), 2.65-2.50 (m, 2H minor), 1.08 (s, 9H minor), 1.03 (s, 9H major), 0.98-0.80 (m, 2H major and 2H minor), −0.06 (s, 9H major), −0.08 (s, 9H minor); LCMS (M+H)+: 662.1.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].O=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][O:18][C:17]2[CH:26]=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:28]=[CH:29][C:16]1=2>C1COCC1.C(OCC)(=O)C>[CH2:33]([O:32][C:30]([C:27]1[CH:28]=[CH:29][C:16]2[C:15](=[CH:3][C:1]#[N:2])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]=2[CH:26]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)c1ccc2c(c1)OCc1ccccc1C2=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)OCc1ccccc1C2=CC#N
Reaction time: 1 h
Yield: 58 %

Procedure:
Diethyl (cyanomethyl)phosphonate (52 ml) was dissolved in 200 ml of THF, and 12.8 g of sodium hydride (60% oily) was added to the solution under ice cooling, followed by stirring for one hour. To the mixture was added 200 ml of a solution of 17.3 g of ethyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-3-carboxylate in THF, and the mixture was heated under reflux for 3 hours. After cooling, ice chips were added to the reaction mixture, and the mixture was then diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (2/1)] to give 11.5 g (58%) of the product as a colorless oily substance.
Reaction SMILES: [CH3:1]I.[CH2:3]1[O:22][C:6]2([C:11]3[CH:12]=[CH:13][C:14]4[C:19]([C:10]=3[S:9](=[O:21])(=[O:20])[NH:8][CH2:7]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:5][CH2:4]1.[OH-].[Na+].O>C(O)(C)C>[CH2:3]1[O:22][C:6]2([C:11]3[CH:12]=[CH:13][C:14]4[C:19]([C:10]=3[S:9](=[O:21])(=[O:20])[N:8]([CH3:1])[CH2:7]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:5][CH2:4]1
Reactant: O=S1(=O)NCC2(OCCO2)c2ccc3ccccc3c21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CN1CC2(OCCO2)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 8 h
Yield: 95 %

Procedure:
14.2 gm (0.1 mol) of methyl iodide were added dropwise, while stirring, to a solution of 11.6 gm (0.04 mol) of 2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide-ethylene ketal in a mixture of 150 ml of isopropanol, 44 ml of 1 N sodium hydroxide and 36 ml of water. The resulting mixture was allowed to stand overnight, and the crystals which separated out were suction-filtered off washed with a mixture of isopropanol an ater (ratio by volume 2:1) and dried in vacuo, yielding 11.6 gm (95% of theory) of 2-methyl-2H-naphtho [2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide-ethylene ketal, m.p. 169°-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[C:21]([CH2:22][NH:23][C:24](=[O:41])[C@H:25]([CH2:37][CH:38]([CH3:40])[CH3:39])[NH:26]C(OCC3C=CC=CC=3)=O)=[CH:20][N:19]=[CH:18]2)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[BrH:42].[CH2:43](OCC)C>C(O)(=O)C>[BrH:42].[BrH:42].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[C:21]([CH2:22][NH:23][C:24](=[O:41])[C@H:25]([CH2:37][CH:38]([CH3:39])[CH3:40])[NH2:26])=[CH:20][N:19]=[C:18]2[CH3:43])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCc1cncn1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: Cc1ncc(CNC(=O)[C@@H](N)CC(C)C)n1-c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
0.40 g of 5-chloro-2'-fluoro-2-[5-[(N-benzyloxycarbonyl-L-leucyl)aminomethyl]-1-imidazolyl]benzophenone was treated with a 35% solution of hydrogen bromide in glacial acetic acid for 45 minutes. Dry diethyl ether was then added, an oily solid being obtained. The product was precipitated from methanol/ethyl acetate, dissolved in water and freeze-dried. There was obtained 5-chloro-2'-fluoro-2-[5-(L-leucylaminomethyl)-2-methyl-1-imidazolyl]benzophenone dihydrobromide in a yield of 0.25 g (60%); [α]D20 = -5.5° (c = 0.2708 in water).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(C)c1cc(F)c(C)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)c1cc(F)c(CBr)cc1F
Yield: 106.3 %

Procedure:
A solution of compound (31a) (3.3 g, 15.4 mmol) in carbon tetrachloride (100 mL) was treated with N-bromosuccinimide (NBS) (3.3 g, 18.5 mmol) in the presence of a catalytic amount of azo(bis)isobutyronitrile (AIBN) (0.05 g, 0.02 mmol). The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution to give 4.8 g (90%) of compound (32a) as clear red oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].I[CH2:26][CH2:27]C>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:26][CH3:27]
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Reactant: CCCI
Product: CCCCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting 1-iodopentane for 1-iodopropane while making non-critical variations the title compound was obtained as 361 mg (71%) of a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.83 (br s, 1H), 7.36-7.28 (m, 3H), 7.17-7.13 (m, 1H), 7.05-7.01 (m, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 3.95-3.85 (m, 2H), 3.12-3.10 (m, 1H), 3.06-3.04 (m, 1H), 2.98-2.93 (m, 2H), 2.88-2.85 (m, 1H), 2.81-2.79 (m, 1H), 2.42-2.37 (m, 2H), 1.59-1.52 (m, 2H), 1.21-1.13 (m, 4H), 0.79 (t, J=7.0 Hz, 3H); HRMS (FAB) calcd for C23H28N2O+H1: 349.2280 found 349.2280.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][N:13]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[O:28])[N:20]([CH3:27])[C:21]2=[O:26])[C:14](Cl)=[O:15].N1C=CC=CC=1>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH:11][C:14]([N:13]([CH3:12])[C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:28])[N:20]([CH3:27])[C:21]3=[O:26])=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CN1C(=O)c2cccc(N(C)C(=O)Cl)c2C1=O
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CN1C(=O)c2cccc(N(C)C(=O)NNc3ccc([N+](=O)[O-])cc3)c2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.4 %

Procedure:
p-Nitrophenylhydrazine (1.5 g, 10 mmole), N-methyl-N-(2-methyl-1,3-dioxoisoindolin-4-yl) carbamoyl chloride (2.5 g, 10 mmole) and 2 ml pyridine were combined in 25 ml dry acetonitrile, heated to reflux, then stirred at room temperature for 4 hours. The solid formed was collected and washed with ether to give 2.6 g of product, m.p. 194°-196° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[I:9])[NH2:5].C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][N:21]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([I:9])=[C:2]([CH3:1])[CH:3]=2)=[O:25])=[CH:22][N:21]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1cc(N)ccc1I
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Yield: 86 %

Procedure:
A solution of 3-methyl-4-iodoaniline (660 mg 2.84 mmol), diisopropylethyl amine (1.2 mL 8.52 mmol) and a catalytic amount of DMAP in CH2Cl2 (15 mL) was treated with 6-chloronicotinoyl chloride (500 mg, 2.84 mmol). Upon completion of the reaction, as judged by TLC, the mixture was partitioned between CH2Cl2 and water. The EtOAc layer was dried over Na2SO4 filtered and concentrated. The solid residue was washed with hexanes and then was passed through a silica gel plug with 50% EtOAc in hexanes as the elution solvent to afford the product, 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide. (910 mg, Yield 86%).