Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#N.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[CH:17]=[CH:16][C:1]([C:3]2[CH:8]=[CH:7][C:6]([O:9][C@H:23]([CH2:18][C@@H:19]([O:24][C:21]3[CH:22]=[CH:23][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:10]#[N:11])=[CH:17][CH:16]=4)=[CH:19][CH:20]=3)[CH3:20])[CH3:22])=[CH:5][CH:4]=2)=[CH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1ccc(O)cc1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Product: C[C@@H](C[C@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
The procedure of Example 11 was repeated except that the 4-cyanophenol was replaced with 0.60 g of 4-(4'-cyanophenyl)phenol. The crude product thus obtained was then recrystallized from ethyl alcohol. Thus 0.49 g of optically active (S,S)-2,4-bis[4'-(4"-cyanophenyl)phenoxy]pentane was obtained (m.p.: 139.5° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O>>[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][N:17]1[CH2:18][C@@H:14]([N:12]2[N:11]=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:13]2)[CH2:15][C@H:16]1[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[C:29]#[N:30])[CH2:25][CH2:26]1)=[O:20]
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Reactant: O=Cc1ccccc1Cl
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccccc2Cl)CC1
Yield: 14.4 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 2-chloro-benzaldehyde (20 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (11 mg, 14.4%) as light yellow oil. MS m/e=589.1 (75%); 591.1 (25%) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.ClCC(OC(=O)CCl)=O.[S:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>ClC(Cl)C>[CH3:1][O:2][C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:24]1[S:23][CH:27]=[CH:26][CH:25]=1)=[O:12])=[O:13]
Reactant: c1ccsc1
Reactant: COC(=O)CCCCCCC(=O)O
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: COC(=O)CCCCCCC(=O)c1cccs1
Temperature: 60 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
In 50 ml of dichloroethane were dissolved 9.41 g (0.05 mole) of suberic acid monomethyl ester and 9.83 g (0.0575 mole) of monochloroacetic anhydride. To the resulting solution were added 5.47 g (0.065 mole) of thiophene and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 60° C. for 5 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 11.5 g of 2-(7-methoxycarbonyl-1-oxoheptyl)thiophene.
Reaction SMILES: O=S(Cl)[Cl:3].O[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([CH2:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][C:18]([C:27]#[N:28])=[CH:17][CH:16]=2)[CH:12]=[N:11][CH:10]=1>C(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH2:8][C:9]1[N:13]([CH2:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][C:18]([C:27]#[N:28])=[CH:17][CH:16]=2)[CH:12]=[N:11][CH:10]=1
Reactant: N#Cc1ccc(Cn2cncc2CCCO)c(-c2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2CCCCl)c(-c2ccccc2)c1

Procedure:
To a solution of SOCl2 (0.382 mL, 5.24 mmol) in CH2Cl2 (20 mL) at 0° C. is added 6-[5-(3-hydroxypropyl)imidazol-1-ylmethyl]biphenyl-3-carbonitrile in portion and the resulting white suspension is refluxed for 1.5 h. The mixture is cooled in ice and partitioned between CH2Cl2 and saturated aqueous NaHCO3. The organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated to give an oily foam.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Br:5][CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[BrH:5].[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: Br
Product: CCOC(=O)c1csc(N)n1
Temperature: 45 °C
Yield: 79.2 %

Procedure:
To a stirring suspension of thiourea (6.0 g, 78.8 mmol) in ethanol (80 mL) was added ethyl bromopyruvate (15.4 g, 78.8 mmol). The resulting solution was heated at 45° C. for 23 h. The solution was cooled at 0° C. for 24 h, and the crystals were collected by filtration and washed with cold ethanol to provide the title compound (15.8 g, 79%). 1H NMR (400 MHz, CD3OD) δ7.70 (s, 1H), 4.41 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Br)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:23]3[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COc1c(Br)cnn(-c2cccc(Cl)c2)c1=O
Agent: N
Product: COc1c(-c2ccc(SC)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 6 starting with 2-(3-chlorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting 4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronic acid (yield: 3.3 g, 68%). 1H NMR (300 MHz, DMSO-d6) δ 2.54 (s, 3H), 4.03 (s, 3H), 7.40 (d, J=9.0 Hz, 2H), 7.50-7.64 (m, 5H), 7.73-7.77 (m, 1H), 8.18 (s, 1H). MS (DCI/NH3) m/z 359 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH2:11])[CH3:3].[C:12](Cl)(Cl)=[O:13].Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[C:28]([C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][NH:36][CH2:37]4)=[CH:32][CH:31]=3)[N:27]=[C:26]([NH2:40])[N:25]=2)[CH2:20][CH2:19]1>>[NH2:40][C:26]1[N:27]=[C:28]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][N:36]([C:12]([NH:11][C@@H:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]4[O:4][CH2:2][CH3:3])=[O:13])[CH2:37]3)=[CH:32][CH:31]=2)[CH:29]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)[N:25]=1
Reactant: O=C(Cl)Cl
Reactant: CCO[C@H]1CCCC[C@H]1N
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CCO[C@H]1CCCC[C@H]1NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 55, Step 3 starting from cis-2-ethoxycyclohexanamine HCl salt, phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=494.3.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1)[CH3:3].[Br-:12].[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N+:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1C)([OH:15])=[O:14].N1CCCC[CH2:29]1>C(O)C>[Br-:12].[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N+:21]1[CH:22]=[CH:23][C:24]([CH:29]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N:2]([CH3:1])[CH3:3])=[CH:9][CH:8]=2)=[CH:25][CH:26]=1)([OH:15])=[O:14]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: C1CCNCC1
Reactant: Cc1cccc[n+]1CCCCCC(=O)O
Agent: [Br-]
Solvent: CCO
Product: CN(C)c1ccc(C=Cc2cc[n+](CCCCCC(=O)O)cc2)cc1
Temperature: 60 °C

Procedure:
A mixture of 4-N,N-dimethylaminobenzaldehyde (3 g, 20 mmoles), N-(5-carboxypentyl)picolinium bromide (5.6 g, 20 mmoles) and piperidine (2 mL) in ethanol (100 mL) was heated at 60° C. overnight. The mixture was evaporated to dryness in vacuo. The residue was redissolved in methanol and then precipitated with ether to give the title product (6.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([OH:14])=[O:13])=[O:4].[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[O:13]=[C:12]([O:14][C@@H:23]1[CH:24]2[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]2)[CH2:22]1)[CH:11]([NH:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 2-(2-(methoxycarbonyl)thiophen-3-ylamino)-2-phenylacetic acid (I10) (404 mg, 1.39 mmol), (R)-quinuclidin-3-ol (529 mg, 4.17 mmol), DCC (859 mg, 4.17 mmol) and HOBT (567 mg, 4.17 mmol) in dry THF (25 ml) was stirred at room temperature overnight. THF was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=98/2 to 95/5) recovering diastereomer 1 of C11 (161 mg; 28% yield), and subsequently diastereomer 2 of C11 (127 g, 35% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:21][CH:20]=1>CN1C(=O)CCC1.O>[CH:13]1([O:12][C:4]2[N:3]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:23][CH:24]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(OC2CCCC2)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)Cc1ccc(Nc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 120 °C
Yield: 51.8 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine (0.090 g, 0.34 mmol) and (4-aminophenyl)acetamide (0.076 g, 0.51 mmol) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 1 h. The reaction mixture was cooled, diluted with water (50 mL) affording a solid. The solid was isolated by filtration and chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.067 g, 52%) as a white solid. MW=380.36. M.p. 208-210° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.05 (s, 1H), 7.58 (br d, J=7.5 Hz, 2H), 7.42 (s, 1H), 7.25 (d, J=7.5 Hz, 2H), 6.85 (s, 1H), 6.74 (s, 1H), 5.31 (septet, J=3.0 Hz, 1H), 2.01-1.90 (m, 2H), 1.80-1.66 (m, 4H), 1.65-1.55 (m, 2H); APCI MS m/z 381 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:6][N:7]=1.S(Cl)([Cl:13])=O>>[ClH:13].[Cl:13][CH2:2][C:3]1[N:4]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nccn1C1CC1
Product: Cl
Product: ClCc1nccn1C1CC1
Temperature: 90 °C

Procedure:
To 2-hydroxymethyl-1-cyclopropylimidazole (1.20 g) was added thionyl chloride (12 ml) at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate, to give 2-chloromethyl-1-cyclopropylimidazole hydrochloride (1.49 g) as brown crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][NH2:12])=[CH:7][C:6]=2[CH:13]=1.[C:14]([NH:16][C:17](=[N:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[O:26][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:28][CH:29]=1)SC)#[N:15]>>[C:14]([NH:16][C:17]([NH:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[O:26][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:28][CH:29]=1)=[N:12][CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=2[CH:7]=1)#[N:15]
Reactant: CSC(=NCCSCc1ccc(CN(C)C)o1)NC#N
Reactant: Cc1ccc2oc(CCN)cc2c1
Product: Cc1ccc2oc(CCN=C(NC#N)NCCSCc3ccc(CN(C)C)o3)cc2c1

Procedure:
It was obtained by reacting amine (a) with N-cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]-methyl]thio]ethyl]-S-methyl-isothiourea, as described in Example 2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[SH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28].CN(C)C=O.Cl>O.C(N(CC)CC)C>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][S:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28]
Reactant: O=C(O)c1cccc(S)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (3.00 g), 3-mercaptobenzoic acid (1.47 g) and N,N-dimethylformamide (30 mL) was dropwise added triethylamine (2.13 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals (3.70 g, yield 90%) of 3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzoic acid from a fraction eluted with acetone-hexane (1:1, v/v). Recrystallization from ethyl acetate gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH:34]([N:37]([CH:41]([CH3:43])[CH3:42])[CH2:38][CH2:39]Cl)([CH3:36])[CH3:35].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:39][CH2:38][N:37]([CH:41]([CH3:43])[CH3:42])[CH:34]([CH3:36])[CH3:35])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21)C(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 2-(diisoproplyamino)ethyl chloride hydrochloride (0.50 g) are added. The reaction mixture is heated to 90° C. for 2 h, then allowed to stir at room temperature overnight. A drop of water is added and the mixture is heated for 20 h. An additional equivalent of 2-(diisoproplyamino)ethyl chloride hydrochloride (0.25 g, 1.25 mmol) is added and the mixture is heated at 100° C. for 5 h, and then stirred at room temperature overnight. Water is added and an oily solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-2% MeOH/CHCl3) gave 0.45 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.22 g of the title compound as a solid.
Reaction SMILES: [C:1](C1CC1(N)C(O)=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=[N:42][C:37]2[CH:38]=[CH:39]C=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[OH-:52]>CN(C=O)C>[CH2:4]([O:3][C:1](=[O:2])[NH:42][C:37]1([C:36](=[O:52])[NH2:41])[CH2:39][CH2:38]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [OH-]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: NC1(C(=O)O)CC1C(=O)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a vial was added Cbz-1-aminocyclopropane-1-carboxylic acid (1.00 g, 4.25 mmol) in DMF (10 mL), followed by the addition of DIPEA (137 g, 10.6 mmol) and HATU (1.80 g, 4.73 mmol). The reaction mixture was stirred at room temperature for 15 min, followed by the addition of NH4OH (4 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The yellow solid residue was dissolved in EtOAc/H2O. The organic phase was separated, washed with water, brine, dried over anhydrous Na2SO4, filtered, concentrated and dried under high vacuum to afford 935 mg of (1-carbamoyl-cyclopropyl)-carbamic acid benzyl ester as a light yellow solid, m/z 235.8 [M+1]+.
Reaction SMILES: [Si]([O:8][C@H:9]([C:47]1[CH:56]=[CH:55][C:54]([OH:57])=[C:53]2[C:48]=1[CH:49]=[CH:50][C:51](=[O:58])[NH:52]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][N:28]2[CH:32]=[N:31][C:30]([C@:33]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)([OH:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:29]2)[CH2:23][CH2:22]1)(C(C)(C)C)(C)C.[F-].[NH4+]>CO>[NH3:11].[CH:41]1([C@@:33]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30]2[N:31]=[CH:32][N:28]([CH2:27][CH:24]3[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:47]4[CH:56]=[CH:55][C:54]([OH:57])=[C:53]5[C:48]=4[CH:49]=[CH:50][C:51](=[O:58])[NH:52]5)[OH:8])[CH2:22][CH2:23]3)[N:29]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCCCCN1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: N
Product: O=c1ccc2c([C@@H](O)CNCCCCCCCCCN3CCC(Cn4cnc([C@](O)(c5ccccc5)C5CCCCC5)n4)CC3)ccc(O)c2[nH]1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
5-[(1R)-1-{[tert-buty(dimethyl)silyl]oxy}-2-({9-[4-({3-[(R)-cyclohexyl(hydroxy)phenylmethyl]-1H-1,2,4-triazol-1-yl}methyl)piperidin-1-yl]nonyl}amino)ethyl]-8-hydroxyquinolin-2(1H)-one (Preparation 8, 13.06 g, 16.06 mmol) was dissolved in methanol (430 ml) and ammonium fluoride (2.97 g, 80.3 mmol) was added. After stirring at 40° C. for 18 hours the solvent was removed in vacuo and the residue partitioned between dichloromethane/methanol (950 ml/50 ml) and saturated aqueous sodium bicarbonate solution (500 mL). The organic layer was separated and the aqueous layer further extracted with dichloromethane/methanol (450 ml/50 ml). The combined organic layers were dried over magnesium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (90:10:1, by volume) to furnish the title compound as a yellow foam, in 72.3% yield, 8.12 g.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14].C(N(CC)CC)C>C(O)C>[N+:8]([C:7]1[C:2]([NH:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NCC(O)c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1NCC(O)c1ccccc1
Yield: 5.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (20.0 g, 0.13 mole), 2-amino-1-phenylethanol (20.74 g, 0.15 mole), and triethylamine (17.5 ml, 0.13 mole) in 200 ml of absolute ethanol was heated to reflux for 11/2 hours. The reaction mixture was filtered and evaporated to dryness. The residue was partitioned between water and methylene chloride (2×). The methylene chloride layers were combined and extracted with water. The methylene chloride layers were dried, filtered, and evaporated to a solid (30.8 g, 94.5%). A 2.4-g sample was recrystallized from methanol and water to give a yellow solid, which was collected by filtration, washed with water, and dried under high vacuum overnight to give 1.8 g of the compound, mp 101°-103° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH2:16].[CH3:17]CCCC>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH:17]([C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: O
Reactant: CCOC(=O)C1(c2cccc(Br)c2)CC1
Reactant: CCCCC
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: CCOC(=O)C1(c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Ethyl 1-(3-bromophenyl)cyclopropanecarboxylate (538 mg, 1.9 mmol) was dissolved in acetone (20 mL). Osmium tetroxide (17.1 μL, 0.07 mmol) and NaIO4 (1.1 g, 5.6 mmol) were added followed by water (10 mL). The reaction mixture was stirred at room temperature for 18 h. Water was added (10 mL) followed by pentane (35 mL). The layers were separated and the aqueous layer was extracted with pentane (20 mL×2) and ethyl acetate (20 mL×2). The combined organics were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (pentane/ethyl acetate 95:5) to afford the title compound as an oil (327 mg, 80%). MS (ES+) (M+H) 219.
Reaction SMILES: [NH3:1].[F:2][C:3]([F:15])([F:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11].[Cl:16][C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(O)(=O)C.CS(C)=O>[F:2][C:3]([F:15])([F:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:1][C:26]1[C:17]([Cl:16])=[N:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:25]=1)(=[O:12])=[O:11]
Reactant: N
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CO
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a 7 mol/L solution of ammonia in methanol (4.0 mL), 2-(trifluoromethyl)benzenesulfonyl chloride (200 mg, 0.818 mmol) was added and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, 2,3-dichloroquinoxaline (162 mg, 0.818 mmol), potassium carbonate (113 mg, 0.818 mmol) and dimethyl sulfoxide (5.0 mL) were added to the residue, and the mixture was stirred at 150° C. for 1 hour. The reaction mixture was slowly added to a mixture (50 ml) of a 1% aqueous acetic acid solution and ice, and the mixture was stirred for 3 hours. The resulting solid was collected by filtration and purified by preparative thin-layer chromatography (chloroform/methanol=19/1). Further, slurry purification was performed using hexane, to give 2-(trifluoromethyl)-N-{3-chloroquinoxalin-2-yl}benzenesulfonamide (Compound AC) (97.0 mg, yield: 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=O)[N:7]([CH3:13])[C:6]=2[CH:14]=1.C(O)C.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[O:10][CH:9]([CH3:11])[CH2:8][N:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: COC(=O)c1cc(Cl)cc2c1OC(C)C(=O)N2C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1CN(C)c2cc(Cl)cc(C(=O)O)c2O1
Yield: 93.6 %

Procedure:
A mixture of 5.1 g of methyl 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate, 20 ml of ethanol and 50 ml of 4% aqueous potassium hydroxide solution is refluxed with heating for 5 hours. The resultant solution is cooled and 350 ml of water is added thereto followed by filtration. The filtrate is made acid with concentrated hydrochloric acid. The precipitated crystals are collected by filtration, washed with water and dried, and then recrystallized from ethanol to give 4.28 g of 6-chloro-3,4-dihydro-2,4-dimethyl-2H-1,4-benzoxazine-8-carboxylic acid, melting at 191°14 193° C.