Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[C:40]([O:44][C:45](=[O:49])[CH2:46][NH:47][CH3:48])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:40]([O:44][C:45](=[O:49])[CH2:46][N:47]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:48])([CH3:43])([CH3:42])[CH3:41]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1OC(=O)C(=CN(C)CC(=O)OC(C)(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added sarcosine tert butyl ester hydrochloride (84 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 577 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:20][CH2:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:23]=1[N:37]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:43]=2)[C:38]1=[O:50])(=O)C>>[C:46]([C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:50])[N:37]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][N:14]=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:22]=1[CH2:21][OH:20])[CH2:45]2)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Reactant: Cn1cc(Br)cc(Nc2ccncn2)c1=O
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccncn2)c1=O
Yield: 38 %

Procedure:
Using the same general procedure as in Example 105, reaction of 107a (250 mg, 0.889 mmol) with 103f (495 mg, 1.07 mmol) afforded 107 in 38% yield (166 mg) as an amorphous off-white solid: mp 216-218° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.65 (s, 1H), 8.30 (d, J=5.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.62 (dd, J=8.0, 1.5 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.46 (dd, J=7.5, 1.0 Hz, 1H), 7.40 (dd, J=7.5, 1.5 Hz, 1H), 7.32 (dd, J=6.0, 1.0 Hz, 1H), 4.95 (s, 2H), 4.92 (t, J=4.5 Hz, 1H), 4.34 (d, J=5.0 Hz, 2H), 3.61 (s, 3H), 1.37 (s, 9H); MS (ESI+) m/z 496.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:11]=[C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[O:9][N:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[CH:11]=[C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[O:9][N:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cc(Cn3ncc(N)n3)on2)OCCO1
Product: CC(=O)c1cc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)on1

Procedure:
Following general procedure A followed by L (with a reaction time of 3 weeks), starting from 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-isoxazol-5-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1(O)[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11]1.Cl>>[CH3:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1
Reactant: Cc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1C
Agent: Cl
Product: Cc1cccc(C2=CN(Cc3ccccc3)CCC2)c1C
Yield: 12 %

Procedure:
A mixture of 7 parts of 3-(2,3-dimethylphenyl)-1-(phenylmethyl)-3-piperidinol hydrochloride and 200 parts of a hydrochloric acid solution 6N was stirred and refluxed overnight. The reaction mixture was evaporated. Water was added and the base was liberated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and ethanol (98:2 by volume) as eluent. The first fraction was collected and the eluent was evaporated, yielding 0.7 parts (12%) of 5-(2,3-dimethylphenyl)-1,2,3,4-tetrahydro-1-(phenylmethyl)pyridine as a residue (intermediate 45).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[CH2:7]([C:9]([CH3:11])=O)[CH3:8].C([O-])(=O)C.[Na+]>O>[CH3:8][C:7](=[N:2][NH:3][C:4]([NH2:6])=[O:5])[CH2:9][CH3:11]
Reactant: CCC(C)=O
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCC(C)=NNC(N)=O
Yield: 71.1 %

Procedure:
To a solution of semicarbazide HCl (61.2 g, 534 mmol), ethyl-methyl ketone (35 g, 0.49 mol) in water (525 mL), sodium acetate (79.7 g, 972 mmol) was added at room temperature and maintained for 18 hours. The reaction mixture was filtered, the obtained solid was washed with ether (2×25 mL) and dried at 70° C. for 20 hours to afford butan-2-one semicarbazone (45 g, 72%) as white solid. 1H NMR (CDCl3) δ 7.9 (br, 1H), 5.0-6.0 (br, 2H), 2.3 (q, 2H), 1.82 (s, 3H), 1.1 (t, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:15][O:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2[NH2:27])[N:21]=1>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:27][C:26]3[CH:25]=[CH:24][S:23][C:22]=3[C:20]3[N:21]=[C:17]([O:16][CH3:15])[S:18][CH:19]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: COc1nc(-c2sccc2N)cs1
Reactant: O=C(O)Cc1cccc2cnccc12
Product: COc1nc(-c2sccc2NC(=O)Cc2cccc3cnccc23)cs1

Procedure:
The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid (72 mg, 0.36 mmol) and 2-(2-methoxythiazol-4-yl)thiophen-3-amine (78 mg, 0.36 mmol) according to protocol A. Retention time (min)=3.237, method [7], MS (ESI) 382.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.99 (s, 1H), 9.69 (s, 1H), 8.60 (d, J=6.5 Hz, 1H), 8.39 (d, J=6.5 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.06 (d, J=7.3 Hz, 1H), 7.96 (d, J=5.5 Hz, 1H), 7.89 (dd, J=8.4, 7.3, 1H), 7.15 (d, J=5.5, 1H), 6.70 (s, 1H), 4.26 (s, 2H), 4.17 (s, 3H).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:17]([NH:19][C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH3:16].C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH3:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In the manner described in example 24, one can condense 2-oxo-4-phenylbutyric acid and L-alanyl-L-tryptophan in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-tryptophan.
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1[N:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]2=[N:6][C:5]=1[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([S-:23])[O:22][C:18]=2[CH:17]=1.[K+]>CO>[CH3:3][C:4]1[N:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]2=[N:6][C:5]=1[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([S:23][CH3:1])[O:22][C:18]=2[CH:17]=1
Reactant: CI
Reactant: Cc1ccn2c(C)c(CCc3ccc4nc([S-])oc4c3)nc2c1
Agent: [K+]
Solvent: CO
Product: CSc1nc2ccc(CCc3nc4cc(C)ccn4c3C)cc2o1
Reaction time: 3 h

Procedure:
Methyl iodide (0.38 ml) was added dropwise to a solution of potassium 6-[2-(3,7-dimethylimidazo[1,2-a]-pyridin-2-yl)ethyl]-2-benzoxazolethiolate (2.00 g) in methanol (30 ml) under ice-water cooling. After being stirred for 3 hours keeping the temperature below 5° C., the solvent was evaporated in vacuo. The residue was mixed with water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 6-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-methylthiobenzoxazole (1.31 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24]1.CN(C=O)C.[H-].[Na+]>C(O)(=O)C>[CH3:22][N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][O:29][C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=2[F:16])[CH2:24]1
Reactant: CN1CCC(CO)C1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN1CCC(COc2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C

Procedure:
To a mixture of 596 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 460 mg of 1-methyl-3-hydroxymethylpyrrolidine and 5 ml of DMF was added 262 mg of 55% sodium hydride while the former was stirred at room temperature. After the resultant mixture was stirred for 1 hour at room temperature, 360 mg of acetic acid was added and DMF was distilled off under reduced pressure. The residue was purified by chromatography on silica gel (chloroform/methanol: 3/1), followed by recrystallization from ethanol. The title compound was obtained as pale green powder (yield: 240 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:23]([OH:25])[CH3:24].[H-].[Na+].O>CS(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([O:25][CH2:23][CH3:24])=[N:3][CH:4]=[CH:5]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CCO
Reactant: O=S(=O)(Nc1ccc2c(Cl)nccc2c1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1nccc2cc(NS(=O)(=O)c3ccc(Cl)cc3)ccc12
Temperature: 80 °C
Reaction time: 9 h

Procedure:
1-Chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (Synthetic Example 61b, 57 mg) was dissolved in dimethyl sulfoxide (1 ml). Ethanol (0.1 ml) and 60% sodium hydride (14 mg) were added thereto, followed by heating under stirring at 80° C. for 9 hours. After cooling as it was, water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by preparative TLC and solidified using isopropyl ether, to give the title compound (21 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][CH:5]=1.[Na+].[CH3:17][S:18]([O-:20])=[O:19]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:6][CH:5]=1
Reactant: CS(=O)[O-]
Reactant: COC(=O)c1ccc(OCCCBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCS(C)(=O)=O)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C starting from 4-(3-bromo-propoxy)-benzoic acid methyl ester and methanesulfinic acid sodium salt using DMF as solvent. MS (ES+) 273.1.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]#[N:12].C(N(CC)CC)C.[CH2:20]([N:24]=[C:25]=[O:26])[CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:20]([NH:24][C:25](=[O:26])[NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]#[N:12])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN=C=O
Reactant: N#Cc1c(N)sc2c1CCCC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Nc1sc2c(c1C#N)CCCC2
Temperature: 80 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
A mixture of 5.35 g (30 mmol) of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (prepared according to Intermediate 1e), 2.0 ml (45 mmol) of triethylamine, 10 ml (90 mmol) of n-butyl isocyanate and 100 ml of toluene was stirred for 16 hours at 80° C. The solid formed was then isolated and was recrystallized from ethanol. Yield: 18%; mp.: 170°-171° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:27][S:28][C:29]1[N:36]2[C:32]([S:33][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:35]2)=[C:31]([S:50][CH3:51])[N:30]=1>>[CH3:27][S:28][C:29]1[N:36]2[C:32]([S:33][C:34]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[CH:35]2)=[C:31]([S:50][CH3:51])[N:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(SC)nc(SC)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: CSc1nc(SC)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Yield: 61.1 %

Procedure:
The procedure of Example 1a) was repeated, except that 762 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.10 g of 5,7-bis(methylthio)-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 720 mg of 4-nitrobenzyl (1S,5R,6S)-2-[5,7-bis(methylthio)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].CCN(C(C)C)C(C)C.[CH2:22]([NH:24][C:25]([N:27]1[N:31]=[CH:30][C:29]2([CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:28]1)=[NH:26])[CH3:23]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:26]=[C:25]([N:27]2[N:31]=[CH:30][C:29]3([CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:28]2)[NH:24][CH2:22][CH3:23])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCNC(=N)N1CC2(C=N1)CCCC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=NS(=O)(=O)c1cccc(C#N)c1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 3.50 g 3-cyanobenzenesulfonyl chloride in 150 mL DCM were added 17.69 mL (6.0 equiv.) DiPEA and 4.00 g (1.0 equiv.) N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine. The reaction mixture was stirred overnight at room temperature and extracted with water. The organic phase was dried over Na2SO4 and evaporated, and the residue was purified by automated flash chromatography (EtOAc/PA 1:1) to give 3.54 g (57%) of a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.17 (t, J=8 Hz, 3H), 1.65-1.86 (m, 8H), 3.41-3.50 (m, 2H), 3.87 (br.s., 2H), 6.70-6.80 (br.s., 1H), 6.87 (s, 1H), 7.60 (t, J=8 Hz, 1H), 7.77 (d, J=8 Hz, 1H), 8.17 (d, J=8 Hz, 1H), 8.23 (br.s., 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:17](O)=O.N>>[N:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:17]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1cnccn1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3cnccn3)n2)c1

Procedure:
The titled compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and pyrazine-2-carboxylic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 8.60 (dt, J=8.0, 1.9 Hz, 1 H), 8.77 (dd, J=5.0, 1.8 Hz, 1 H), 8.86-8.89 (m, 1 H), 8.89-8.91 (m, 1 H), 9.34 (dd, J=2.4, 0.8 Hz, 1H), 9.56 (d, J=1.6 Hz, 1 H) ppm; MS (DCI/NH3) m/z 226 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(Br)c(F)c1
Yield: 90.5 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and diethylamine (0.38 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N,N-diethyl-3-fluorobenzenesulfonamide (0.41 g, 90%) was provided after purification. HRMS: calcd for C10H13BrFNO2S, 308.98344; found (EI, M+.), 308.9822. HPLC purity 100.0% at 210-370 nm, 10.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[S:4][N:3]=1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)[S:4][N:3]=1
Reactant: Cc1nsc(N2CCC3(CC2)OCCO3)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nsc(N2CCC(=O)CC2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of 8-(3-methyl-[1,2,4]thiadiazol-5-yl)-1,4-dioxa-8-aza-spiro[4.5]decane (1.75 g, 7 mmol) in acetone (15 mL) was added 2 N aqueous HCl solution (50 mL) and stirred at 50° C. for 3 hours. The reaction mixture was cooled to 0° C. and saturated aqueous NaHCO3 solution was added dropwise until pH 7. The aqueous phase was extracted three times with dichloromethane, the combined organic phases were dried over sodium sulfate and the solvent was evaporated to give the title compound as a light brown solid (1.29 g, 90%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:11][O:10][C:9]1=[O:21])=[O:7].[CH3:22][CH:23]([CH3:39])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1)=[O:25]>>[F:20][C:15]1[CH:14]=[C:13]([C@@H:12]2[CH2:11][O:10][C:9](=[O:21])[N:8]2[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:36]2[CH2:37][CH2:38][CH:33]([C:29]3[CH:28]=[C:27]([NH:26][C:24](=[O:25])[CH:23]([CH3:22])[CH3:39])[CH:32]=[CH:31][CH:30]=3)[CH2:34][CH2:35]2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: O=C(CCCCCl)N1C(=O)OC[C@H]1c1ccc(F)c(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)N3C(=O)OC[C@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (4R)-3-(5-chloropentanoyl)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[NH2:3].[C:13](/[C:15](=[CH:21]\OCC)/[C:16]([O:18][CH2:19]C)=[O:17])#[N:14].C([O-])(=O)C.[Na+].O>CN(C=O)C>[CH3:19][O:18][C:16]([C:15]1[CH:21]=[N:3][N:2]2[C:4]3[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6](=[O:8])[NH:14][C:13]=12)=[O:17]
Reactant: NNc1ccccc1C(=O)O
Reactant: CCO/C=C(\C#N)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnn2c1[nH]c(=O)c1ccccc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 2-hydrazinylbenzoic acid hydrochloride (1.05 g, 5.57 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.9 g, 5.32 mmol) and sodium acetate (0.457 g, 5.57 mmol) in DMF (7 mL) was heated to 140° C. for 2 h then cooled. Water (5 mL) was added and the mixture was stirred at ambient temperature for 1 h then filtered. The solid was washed with H2O, EtOH and Et2O then dried.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=2[CH:18]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:23]3[CH2:24][CH2:25][C:19]4[CH:18]=[C:17]([O:16][CH3:15])[C:27]([O:28][CH3:29])=[CH:26][C:20]=4[CH2:21][CH2:22]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1OC)CCN(C[C@H](O)COc1cccc3[nH]ccc13)CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 48% overall yield. FDMS m/e=396 (M+ of free base). α[D]589 =-9.34 (c=0.47, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Li]CCCC>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1
Reactant: C=Cc1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Li]CCCC
Product: COc1ccccc1N1CCN(CCc2ccccc2)CC1

Procedure:
According to GP, 2.22 mmol (=0.43 g) of 1-(2-methoxyphenyl)piperazine and 2.22 mmol (=0.23 g=0.25 ml) of styrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (1:2) gives the product 1-(2-methoxyphenyl)-4-(2-phenyl-1-ethyl)piperazine as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)\[C:7]([O:9][CH2:10][CH3:11])=[O:8].BrCCBr.[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C=O)C>[N:41]([CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)\[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCCN=[N+]=[N-])c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
The starting material was prepared as follows. Using the procedure of Footnote 15, ethyl 2-((Z)-2-bromoethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetate was prepared from 1,2-dibromoethane, and reacted with sodium azide in DMF solution. Purification by chromatography gave ethyl 2-((Z)-2-azidoethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetate, which was dissolved in 1,2-dimethyoxyethane and hydrogenated using 5% w/w palladium on charcoal as catalyst at ambient temperature and pressure for 16 hours. Catalyst was filtered off, and the solution was treated with bis(O-t-butyl)carbonic anhydride at ambient temperature. After 48 hours, the reaction was worked up conventionally, and the product isolated by chromatography on silica, eluting with 60:40 v/v hexane:EtOAc. The ethyl ester was saponified (see Footnote 15) to give 2-((Z)-2-t-butoxycarbonylaminoethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid, having the following n.m.r. in CDCl3 : 1.33(s, 9H); 3.37(m, 2H); 4.27(t, 2H); 5.38(br s, 1H); 6.59(s, 1H); s, 1H); 7.29(m, 16H).