Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([CH2:15][C:16]#[N:17])[CH2:8]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[C:22]([Cl:37])=[CH:21][N:20]=1.Cl.O1CCOCC1>CC(O)C>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:10](=[CH:11][CH:12]=2)[CH:9]2[CH2:13][CH2:14][CH:5]3[CH2:6][N:7]([CH2:15][C:16]#[N:17])[CH2:8]2)=[N:20][CH:21]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: N#CCN1CC2CCC(C1)c1cc(N)ccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(CC#N)C2)ncc1Cl
Temperature: 130 °C

Procedure:
(4-Amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-acetonitrile (30 mg, 0.132 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (48.3 mg, 0.145 mmol, 1.1 eq) were dissolved in IPA (1.2 mL). 4.0 M HCl in dioxane (36 μL, 0.145 mmol, 1.1 eq) was added and the reaction was heated at 130° C. in a microwave for 20 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by preparative HPLC using a gradient of 5-75% acetonitrile/water as the eluting solvent to obtain 2-[5-chloro-2-(10-cyanomethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide as an orange film (13 mg, 19%). LCMS (m/e) 524 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.11 (s, 1H), 8.48 (d, 1H, J=8.3 Hz), 8.07 (s, 1H), 7.95 (dd, 1H, J=1.5 and 8.0 Hz), 7.60-7.53 (m, 1H), 7.35-7.20 (m, 3H), 7.05-6.99 (m, 2H), 4.86 (bs, 1H), 3.55 (s, 2H), 3.10-3.01 (m, 1H), 2.99-2.91 (m, 1H), 2.91-2.83 (m, 2H), 2.64 (s, 3H), 2.58 (d, 2H, J=9.9 Hz), 2.15 (d, 2H, J=8.3 Hz), 1.68 (d, 2H, J=9.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:1]([C:2]2[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=2)[S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(F)cc1)N(c1cc(Br)cnc1Cl)S(=O)(=O)c1ccc(F)cc1
Yield: 85.8 %

Procedure:
A solution of 3-amino-5-bromo-2-chloropyridine (0.94 g, 4.5 mmol) (Oakwood Products, Inc., West Columbia, S.C.) and 4-fluorobenzenesulfonyl chloride (Aldrich, St. Louis, Mo.) (1.73 g, 8.9 mmol) in pyridine (20 mL) was heated in a microwave tube at 100° C. for 15 minutes. The mixture was concentrated in vacuo and the residue was washed with EtOAc containing small amount of MeOH to give the desired product as a white solid (2.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[S:38][C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[S:38][C:34]([CH3:33])=[CH:35][N:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)s5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 1 eq), 1-(5-methylthiazol-2-yl)cyclopropanamine (0.07 g, 1 eq), EDCI.HCl (0.13 g, 1.5 eq), HOBT (0.094 g, 1.5 eq) and TEA (0.19 ml, 3 eq) were dissolved in dichloromethane and the above solution was stirred at room temperature for 18 h. Then water was added to the mixture and the organic layer was separated. The organic layer was washed with water and the product was purified by Prep. HPLC. Yield: 65 mg (25%) 1H NMR (400 MHz, CDCl3): δ 1.43-1.46 (m, 2H), 1.74-1.77 (m, 2H), 2.32 (s, 3H), 2.37 (s, 3H), 3.01-3.03 (d, J=5.2 Hz, 3H), 4.04 (s, 3H), 5.89 (m, 1H), 6.91 (s, 1H), 7.16 (t, 2H), 7.27 (m, 2H), 7.51 (d, J=4 Hz, 1H), 7.66 (s, 1H), 8.00 (m, 2H), 8.13 (s, 1H), 8.7 (s, 1H). LCMS: (ES+) m/z=570.2 (M+H).
Reaction SMILES: [C:1]([C:3]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.S(=O)(=O)(O)O>O>[C:1]([C:3]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2cccc3ccccc23)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(c2cccc3ccccc23)CCC(=O)CC1
Yield: 76 %

Procedure:
A mixture of 16.73 g. (0.055 mole) of methyl 5-cyano-5-(1-naphthyl)-2-oxocyclohexanecarboxylate (prepared in Example 11) in 400 ml. of acetic acid and 200 ml. of 10% sulfuric acid is stirred mechanically for about 44 hours. The mixture is then allowed to cool and diluted with water. This mixture is extracted thoroughly with benzene. The organic layer is successively washed with water, sodium bicarbonate solution and brine and evaporated to dryness. The solid residue is recrystallized from acetone to give 10.3 g. (76% yield) of 4-cyano-4-(1-naphthyl)cyclohexanone, having a melting point of 213° to 215°C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(Cc3ccc(C#N)cc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.050 g (0.112 mmol) of {3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-piperazin-1-yl-methanone, hydrochloride salt was dissolved in 3 ml of DMF. 61.9 mg (0.448 mmol) of potassium carbonate was added to the solution, followed by 0.022 g (0.11 mmol) of 4-bromomethyl-benzonitrile. The reaction solution was shaken for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with water and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1), and DCM/MeOH (10/1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)[CH3:2].Cl[C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:32][C:31]1[C:26]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([N:6]4[C@H:5]([CH2:4][O:3][CH2:1][CH3:2])[CH2:9][O:8][C:7]4=[O:10])=[CH:12][CH:13]=3)=[O:18])[CH2:24][CH2:23]2)=[N:27][CH:28]=[C:29]([Cl:33])[CH:30]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)cc1
Yield: 59.5 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-ethoxymethyl-3-[4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (1.39 g) described in Preparation Example 167 and 2,3,5-trichloropyridine (1.53 g), the title compound (1.19 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[C:4](=[O:17])[C:3]=1[C:18]#[N:19].[C:20]([O:24][C:25]([N:27]1[CH2:30][CH:29]([NH2:31])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[H-].[Na+]>>[C:20]([O:24][C:25]([N:27]1[CH2:30][CH:29]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[C:4](=[O:17])[C:3]=2[C:18]#[N:19])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOCCn1c(=O)c(C#N)c(Cl)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: [H-]
Agent: [Na+]
Product: CCOCCn1c(=O)c(C#N)c(NC2CN(C(=O)OC(C)(C)C)C2)c2ccccc21
Reaction time: 2 h

Procedure:
To a stirred solution of 4-Chloro-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1 eq, 0.100 g, 0.36 mmole) in N,N′-dimethylfomamide was added commercially available 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (1.1 eq, 0.068 g, 0.39 mmole) and treated with 60% NaH oil dispersion (1.5 eq, 0.013 g, 0.54 mmole). After stirring for 2 h, reaction was quenched with 10% HCl aq. (1 ml) then H2O (5 ml). A solid formed that was collected and dried. No further purification was necessary, afforded 3-[3-Cyano-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinolin-4-ylamino]-azetidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (0.133 g, 90%, calc M+H 413, obs M+H 413).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].[C:29](#[N:33])[CH2:30][C:31]#[N:32]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:33][C:29]1[N:22]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=2[O:18][CH3:17])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:30]=1[C:31]#[N:32]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#CCC#N
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(N)c(C#N)c(-c3ccccc3)c2-c2ccccc2)c(OC)c1

Procedure:
A solution of benzoin (6.81 g, 32.1 mmol), 2,4-dimethoxybenzylamine (5.37 g, 32.1 mmol) and p-toulenesulfonic acid monohydrate (20 mg, cat.) in toluene (100 mL) was heated to 80° C. for 5 minutes. Malononitrile (2.12 g, 32.1 mmol) was then added and the reaction mixture was heated to reflux for 3 hours using a reflux condenser fitted with a Dean-Stark trap. The solution was then cooled, diluted with ethyl acetate (100 mL), extracted with sodium bicarbonate (conc., aq., 50 mL), hydrochloric acid (0.5N, aq., 50 mL) and water (50 mL), dried, filtered and the filtrate was concentrated under reduced pressure. Chromatography (SiO2, ethyl acetate:hexane 1:2) afforded the title compound as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[CH2:4][NH:5][C:6](=[O:17])[CH:7]([CH2:12][S:13]C(=O)C)[CH2:8][CH:9]([CH3:11])[CH3:10]>C(O)C>[CH3:19][O:18][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6](=[O:17])[CH:7]([CH2:12][SH:13])[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(CNC(=O)C(CSC(C)=O)CC(C)C)OC
Solvent: CCO
Product: COC(CNC(=O)C(CS)CC(C)C)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The N-(2,2-dimethoxyethyl)-2-[(acetylthio)methyl]-4-methylpentanamide obtained in Example 1 is dissolved in 15 ml of absolute ethanol and the atmosphere is purged with argon. Concentrated ammonium hydroxide (2 ml) is added and this solution is stirred at room temperature for 3 hours, concentrated to dryness in vacuo and dried at 50° C. for 8 hours over phosphorous pentoxide. The title compound (0.8 g) crystallizes, melting point 34°-37° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])(=O)[CH3:2].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO>[OH:18][N:17]=[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])[CH3:2]
Reactant: NO
Reactant: COC(=O)c1ccc(C(C)=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(C)=NO)c(OC)c1
Temperature: 40 °C
Yield: 98.3 %

Procedure:
Methyl 4-acetyl-3-methoxybenzoate (0.396 g, 1.90 mmol), hydroxylamine hydrochloride (1.02 g, 14.7 mmol), and sodium acetate (1.21 g, 14.7 mmol) were suspended in methanol (10 mL) and the reaction mixture heated at 40° C. for 4 h. Upon cooling to room temperature the solvent was removed under reduced pressure. The residue obtained was partitioned between ethyl acetate (80 mL) and water (30 mL). The organic extract was washed with water (25 mL) and brine. The washed extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (0.417 g, 98%). LC-MS: (FA) ES+ 224; 1H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 7.61-7.49 (m, 2H), 7.34 (d, J=7.7 Hz, 1H), 3.86 (s, 6H), 2.05 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:24](=[O:25])[CH2:23][C:19]2[O:18][CH:22]=[CH:21][CH:20]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1ccco1
Product: O=C(Cc1ccco1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 57.9 %

Procedure:
Example 38 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and 2-furylacetic acid (0.025 g) to give the title compound (0.044 g).
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:15][C:16]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:17]=1[C:18](O)=[O:19]>>[CH3:15][C:16]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:17]=1[C:18]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:19]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: Cc1ccc(C)c(C(=O)NCCC23CC4CC(CC(C4)C2)C3)c1
Yield: 86.2 %

Procedure:
Prepared according to the method of Example 14 from 1-adamantaneethylamine hydrochloride (0.131 g) and 2.5-dimethylbenzoic acid (0.099 g) to give the title compound as a white solid (0.163 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[C:8]=2[O:12]C)[N:3]=1>Br>[F:14][C:7]1[C:8]([OH:12])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: COc1c(F)ccc2nc(C)ccc12
Agent: Br
Product: Cc1ccc2c(O)c(F)ccc2n1
Yield: 72.6 %

Procedure:
A mixture of 2-methyl-5-methoxy-6-fluoroquinoline (2.07 g, 10.8 mmol) and 48% hydrobromic acid (30 ml) was stirred at reflux for 24 h. The reaction mix was reduced to minimum volume in vacuo and partitioned between dichloromethane (50 ml) and sat. aqueous sodium bicarbonate solution (50 ml). The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound as a brown solid (1.39 g, 73%).
Reaction SMILES: [CH:1]1[C:2]([C:10]#[N:11])=[CH:3][C:4](Br)=[C:5](O)[C:6]=1Br.C1C(C#N)=CC(I)=C([OH:19])C=1I>>[OH:19][C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][C:2]=1[C:10]#[N:11]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Reactant: N#Cc1cc(I)c(O)c(I)c1
Product: N#Cc1ccccc1O

Procedure:
bromoxynil, and ioxynil.
Reaction SMILES: O.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)C>[OH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([NH:2][C:14](=[O:16])[CH3:15])=[CH:4][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)c2ccccc12
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(O)c2ccccc12
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Into a 500 ml round bottom flask (fitted with a magnetic stirrer), a 50:50 mixture of water:ethanol was combined with 4-amino1-naphthol (20 g, 125 mmole) until the solid was completely dissolved. The solution was warmed to boiling, and to it was added acetic anhydride (14 g) and the resulting solution was stirred for 1 hour. Upon cooling, crystals of N-(4-hydroxy-1-naphthyl)acetamide (20 g, 79% yield) formed.
Reaction SMILES: O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:35][NH:36][C:37](=[O:41])[C:38]([NH2:40])=[O:39])=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]1[O:41][C:37]([C:38]([NH2:40])=[O:39])=[N:36][N:35]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
(CF3SO2)2O (0.58 g, 2.08 mmol) was slowly added to a −10° C. solution of 2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoacetamide (0.30 g, 0.83 mmol) and pyridine (0.6 mL) in dry DCM (5 mL). The reaction mixture was allowed to warm to rt. The reaction mixture was stirred at rt for 1 h then quenched with sat. NaHCO3 very slowly. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 1:10 to 2:1 EtOAc/hexane followed by 10:1 to 2:1 petroleum ether/EtOAC) to give 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazole-2-carboxamide (0.18 g, 47%) as a slight yellow solid. ESI-MS (EI+, m/z): 344.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]4[O:16][C:17]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:18][N:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][C:5]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)(O)[CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:14][C:2]1([F:1])[CH2:7][CH2:6][C:5]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)=[CH:4][CH2:3]1
Reactant: OC1(c2cn[nH]c2)CCC(F)(F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FC1(F)CC=C(c2cn[nH]c2)CC1
Yield: 82.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 99b by using the 4,4-difluoro-1-(1H-pyrazol-4-yl)cyclohexanol (0.25 g, 1.24 mmol) prepared in Example 143a, p-toluenesulfonic acid monohydrate (120 mg, 0.62 mmol) and toluene (3.0 mL), to yield the title compound (189 mg, 83%) as a colorless solid.
Reaction SMILES: C([O:4][CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[CH2:7][NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(=O)C.[OH-].[Na+]>CO>[C:11]1([C@H:9]([NH:8][CH2:7][CH:6]([C:17]2[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=2)[CH2:5][OH:4])[CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)OCC(CN[C@H](C)c1ccccc1)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](NCC(CO)c1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of diastereopure 3-((R)-1-phenylethylamino)-2-(4-bromophenyl)propyl acetate (2.85 g, 7.57 mmol) in methanol (30.3 ml) was added 1.0N-sodium hydroxide (30.3 ml, 30.3 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours. The mixture was partitioned between saturated ammonium chloride solution and chloroform, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford diastereopure 3-((R)-1-phenylethylamino)-2-(4-bromophenyl)propan-1-ol as white solid (2.40 g, 95%).
Reaction SMILES: NS(C1C=CC(NC2SC(C#N)=C(N)N=2)=CC=1)(=O)=O.S.[NH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]2[S:33][C:34]([C:38](=[S:40])[NH2:39])=[C:35]([NH2:37])[N:36]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23].Br[CH2:42][C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=O>C(N(CC)CC)C.N1C=CC=CC=1.CO>[NH2:37][C:35]1[N:36]=[C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([S:22]([NH2:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)[S:33][C:34]=1[C:38]1[S:40][CH:42]=[C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:39]=1
Reactant: NC(=S)c1sc(Nc2ccc(S(N)(=O)=O)cc2)nc1N
Reactant: O=C(CBr)c1ccccc1
Agent: N#Cc1sc(Nc2ccc(S(N)(=O)=O)cc2)nc1N
Agent: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CO
Product: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)sc1-c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbonitrile (0.59 g, 2 mmol) in 20% triethylamine/pyridine (50 ml) was bubbled H2S gas at ice-water temperature for 30 minutes. Then the reaction solution was sealed and stirred at room temperature overnight. Argon gas was bubbled through the reaction solution for 60 minutes to replace the H2S, and then the solvents were removed at reduced pressure. The residue was dissolved in EtOAc, and the EtOAc solution was then washed with 5% citric acid (50 ml×3) followed by brine. The solvent was removed in vacuo and the residue was triturated in Et2O. The product 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbothioamide was collected by filtration (0.56 g, 95%). To prepare the title compound, a solution of 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbothioamide (164 mg, 0.5 mmol) and α-bromoacetophenone (110 mg, 0.55 mmol) in MeOH (20 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (50 ml). The EtOAc solution was washed with saturated NaHCO3 (10 ml), followed by brine. Purification of the residue by silica gel chromatography provided 4-(4′-amino-4-phenyl-[2,5′]bithiazolyl-2′-ylamino)-benzenesulfonamide. Mp 233-235° C. (decomp.). 1H NMR (CD3OD): δ7.96 (s, 1H), 7.82 (s, 4H), 7.44-7.25 (m, 4H). ESIMS (MH+): 430; (M−H−): 428.
Reaction SMILES: [C:1]([S:7][CH2:8]/[C:9](=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[O:12]=[C:10]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])/[C:9](/[CH2:8][S:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)O
Reactant: CCOC(=O)CCN
Product: CCOC(=O)CCNC(=O)/C(=C\c1ccccc1)CSC(=O)C(C)(C)C
Yield: 73 %

Procedure:
The (E)-2-pivaloylthiomethyl-3-phenylpropenoic acid described in Example 8 (step B) is coupled with ethyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 73% (after flash chromatography, eluent: ether/petroleum ether 55/45)-oil IR: 3300, 1710, 1650, 1620 cm-1 1H NMR (CDCl3): 7.20 (s, 5H); 6.75 (s, 1H); 6.0 (broad t, 1H); 3.95 (q, 2H, J=7.5 Hz); 3.80 (s, 2H); 3.40 (q app., 2H, J. app=6.40 Hz); 2.35 (t, 2H, J=5.9 Hz); 1.30 to 0.95 (m, 12H). Microanalysis: C20H27NO4S Calc. % C=63.63 H=7.21 N=3.71 Found. % C=63.35 H=7.16 N=3.52