Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Cl)[N:11]=1)[C:5](OC)=O.CNS(C)(=O)=O.Cl[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[N:28]=1)[C:23]([OH:25])=[O:24]>>[CH3:10][N:11]([CH2:2][CH:3]1[CH2:5][CH:4]1[CH3:9])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[N:28]=1)[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CN(c1cc(C(=O)O)cc(Cl)n1)S(C)(=O)=O
Agent: CNS(C)(=O)=O
Product: CC1CC1CN(C)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)n1

Procedure:
Prepared from Methyl 2,6-dichloroisonicotinate, methyl(methylsulfonyl)amine and intermediate 3.3.1 following a similar procedure as described for the preparation of intermediate 4.2c.1. 1H NMR (400 MHz, CD3OD) δ 7.02 (s, 1H), 6.96 (s, 1H), 3.55 (A of ABX, dd, J=14.4, 6.0 Hz, 1H), 3.29 (B of ABX, dd, J=14.4, 7.2 Hz, 1H), 3.35 (s, 3H), 3.15 (s, 3H), 3.12 (s, 3H), 1.03 (d, J=6.0 Hz, 3H), 0.82-0.66 (m, 2H), 0.48-0.41 (m, 1H), 0.28-0.22 (m, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[CH:27]=3)[CH:22]=[N:21]4)=[CH:11][C:10]=2[F:38])[CH2:4][CH2:3]1.C=O.[BH3-][C:43]#N.[Na+]>CO.C(Cl)Cl>[O:39]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH2:37][CH2:36][N:35]([CH3:43])[CH2:34][CH2:33]5)[CH:27]=3)[CH:22]=[N:21]4)=[CH:11][C:10]=2[F:38])[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCN(Cc2c(F)cc(-c3cccc4ncc(-c5cccc(N6CCNCC6)c5)nc34)cc2F)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2cccc(-c3cnc4cccc(-c5cc(F)c(CN6CCS(=O)(=O)CC6)c(F)c5)c4n3)c2)CC1

Procedure:
A solution of 8-[4-(1,1-Dioxido-thiomorpholin-4-ylmethyl)-3,5-difluoro-phenyl]-2-(3-piperazin-1-yl-phenyl)-quinoxaline (as obtained in example 169, 79 mg, 0.137 mmol) in MeOH (3 ml) and CH2Cl2 (1.5 ml) is treated with HCHO (41 μl, 0.550 mmol, 37% in H2O/MeOH 9:1) and NaBH3CN (35 mg, 0.546 mmol) at RT for 2 h. The reaction mixture is concentrated under reduced pressure. The residue is purified by reverse phase prep-HPLC (Waters) to afford the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:13]1[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[CH:11][C:12]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Temperature: 25 °C

Procedure:
To a dried round bottom flask fitted with a condenser was added methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate from Step A of Example 51 (1.50 g; 3.67 mmol) and excess phosphorous oxychloride (4 mL). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was allowed to cool to room temperature, and the volatiles were removed in vacuo. The residue was redissolved in methylene chloride and washed with saturated NaHCO3 solution (2×), water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-10% ethyl acetate:hexane) to afford the desired product: m/e=428 (M+2) Rt=4.42 min on LCMS.
Reaction SMILES: O[C:2]1[C:10]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.IC.[C:18](=O)([O-])[O-:19].[Cs+].[Cs+].[C:24]([O:27][CH2:28]C)(=[O:26])C>CN(C)C=O>[CH3:28][O:27][C:24](=[O:26])[C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:2][C:3]=1[O:19][CH3:18]
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1O
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(F)(F)F)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.0 g 2-hydroxy-(trifluoromethoxy)benzoic acid were dissolved in 30 ml dimethylformamide. 640 mg iodomethane and 4.70 g cesium carbonate were added and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was diluted by addition of 100 ml ethyl acetate, washed with 30 ml water and brine and then dried over MgSO4. The solvent was removed in vacuo to obtain 590 mg 2-methoxy-4-trifluoromethoxy-benzoic acid methyl ester.
Reaction SMILES: C=O.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CCC[C@H:11]1C(O)=O.[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1>CS(C)=O>[C:4]1([N:3]2[CH2:11][C@@H:23]3[CH2:22][CH2:21][C@H:20]2[CH2:19][C:18]3=[O:24])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C1C=CCCC1
Reactant: Nc1ccccc1
Agent: C=O
Solvent: CS(C)=O
Product: O=C1C[C@@H]2CC[C@H]1CN2c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2.4 mL of formaldehyde (36.5% in water), 3.1 mL of aniline and 1.0 g of (S)-proline in 125 mL of DMSO was added 6.0 mL of 2-cyclohexen-1-one. The mixture was stirred for 72 h at rt, quenched with water and extracted with toluene. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The crude product was purified by CC using EtOAc/heptane 1/5 to 1/3 to yield 1.1 g of (1S,4S)-2-phenyl-2-aza-bicyclo[2.2.2]octan-5-one a as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11](Cl)(=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
To 5.0 g of para-nitrophenol in 60 ml of chloroform+ ether (1:1) are added while cooling with ice first 9.4 g of palmitoyl chloride and then 5.0 ml of triethylamine. After having been refluxed for 2 hours, the batch is dissolved in ethyl acetate, and the organic phase is washed with 0.5N-potassium carbonate and water, dried over sodium sulfate and evaporated. On crystallization from ether+petroleum ether, lamellae are obtained which melt at 64°- 65° C.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:64][CH2:65][S:66][C:67]2[N:68]=[N:69][N:70]([CH3:72])[N:71]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:64][CH2:65][S:66][C:67]4[N:68]=[N:69][N:70]([CH3:72])[N:71]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cn1nnc(SCSC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: COc1ccccc1
Product: Cn1nnc(SCSC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)n1
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(2-methyltetrazol-5-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.16 g: 1.12 mMol.) in a mixture of anisole (4 ml) and nitromethane (16 ml) at -40° C. is added a solution of aluminum chloride (1.19 g: 8.95 mMol.) in anisole (4 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is mixed with 1N-hydrochloric acid (9 ml), diluted with water, washed with ethyl acetate, concentrated to remove the remaining organic solvents, and passed through a column of styrene-divinylbenzene copolymer adsorbent. The adsorbed material is eluted with water-methanol (1:4) and concentrated to give powder which is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(2-methyltetrazol-5-ylthiomethylthio)-3-cephem-4-carboxylic acid (466 mg) as yellow powder. Yield: 79%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[CH2:13]([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH2:28][CH2:27][CH2:26][C:25]=2Br)[N:19]=1)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH2:28][CH2:27][CH2:26][C:25]=2[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])[N:19]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cccc(C2=C(Br)CCC2)n1
Reactant: COc1ccc(F)cc1B(O)O
Product: CCOC(=O)c1cccc(C2=C(c3cc(F)ccc3OC)CCC2)n1

Procedure:
Prepared by general procedure B(iii) but using 5-fluoro-2-methoxyphenylboronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid and 6-(2-bromocyclopent-1-enyl)-pyridine-2-carboxylic acid ethyl ester instead of 3-(2-bromocyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:4][CH:3]=1
Reactant: CNC(=O)c1cc(N2CCN(C)CC2)ncc1Br
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(N2CCN(C)CC2)ncc1-c1ccccc1Cl
Temperature: 80 °C
Yield: 63.6 %

Procedure:
To a suspension of 1.20 g (3.83 mmol) 5-bromo-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide in 15 ml toluene were added successively 0.135 g tetrakis(triphenylphosphine)palladium(0), 4 ml 2 M sodium carbonate solution in water and 0.72 g (4.6 mmol) o-chlorphenylboronic acid. The mixture was heated under argon at 80° C. for 18 h. The aqueous layer was separated and washed with toluene. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.84 g (63%) of the title compound as a pale brown foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:33][CH2:34][CH3:35]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:33][CH2:34][CH3:35])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Reaction time: 0.75 h

Procedure:
A solution of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cyclohexyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Example 2, Step 3, 2 g) in anhydrous dimethylformamide (15 ml), under an atmosphere of nitrogen, was treated with sodium hydride (0.22 g of a 55-60% dispersion in mineral oil, 5.1 mmol) in one portion, at 0° C. After 45 min at 0° C., 1-iodopropane (0.55 ml) was added in one portion and the solution allowed to reach ambient temperature and stirred overnight. Solvent was removed under reduced pressure, and the crude residue partitioned between water (25 ml) and dichloromethane (25 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (3×25 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was triturated with diethyl ether to give the title compound (1.74 g). Mp 160°-163° C. 1H NMR (360 MHz, CDCl3) δ 0.82 (3H, t, J=10.5 Hz), 0.94-1.48 (5H, m), 1.50-1.76 (5H, m), 1.79-1.90 (1H, m), 1.96-2.08 (1H, m), 2.70-2.84 (1H, m), 3.46-3.59 (1H, m), 4.22-4.35 (1H, m), 5.06-5.16 (3H, m), 5.07 (1H, d, J=12.0 Hz), 7.21-7.40 (7H, m), 7.44-7.59 (2H, m).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31](O)=[O:32])[CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[N:67]1([S:79]([NH2:82])(=[O:81])=[O:80])[CH2:72][CH2:71][CH:70]([CH:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[C:31](=[O:32])[N:76]3[CH2:75][CH2:74][CH:73]([CH:70]4[CH2:71][CH2:72][N:67]([S:79](=[O:81])(=[O:80])[NH2:82])[CH2:68][CH2:69]4)[CH2:78][CH2:77]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1
Reactant: NS(=O)(=O)N1CCC(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(S(N)(=O)=O)CC3)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 73 mg (0.14 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 51 mg (0.16 mmol) TBTU, 42 μL (0.3 mmol) triethylamine and 41 mg (0.14 mmol) [4,4′]bipiperidinyl-1-sulphonic acid amide (used as the hydrochloride salt) in 1.8 mL DMF was stirred overnight at RT. The reaction mixture was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC(N(C)C)=C(C)C.C(N(CC)C(C)C)(C)C.[C:41]([O:45][C:46](=[O:49])[CH2:47][NH2:48])([CH3:44])([CH3:43])[CH3:42]>ClCCl>[C:41]([O:45][C:46](=[O:49])[CH2:47][NH:48][C:14]([C:13]1[CH:12]=[N:11][C:10]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:17]=1)=[O:15])([CH3:44])([CH3:43])[CH3:42]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a suspension of 3.66 g 5-(3,4-dichloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid in 40 ml dichloromethane was added 1.469 g Ghosez's reagent ((1-chloro-2-methyl-propenyl)-dimethyl-amine)) and the mixture was stirred at ambient temperature for 30 min. To the resulting solution was added 3.224 g N,N-diisopropylethylamine and 1.44 g glycine-t-butylester and the mixture was stirred at ambient temperature for 30 min. The reaction mixture was quenched by addition of 10% aqueous citric acid. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=9:1 to 1:1 to yield 4.10 g of the title compound as white foam. MS (EI): 477.0608 (M−H).
Reaction SMILES: C1C[CH2:5][CH:4]([N:7]=[C:8]=NC2CCCCC2)[CH2:3][CH2:2]1.C1C=CC2N([OH:25])N=NC=2C=1.[CH3:26][NH:27][C:28](=[S:31])[NH:29][NH2:30]>O1CCCC1>[CH3:26][N:27]1[C:2]([C:3]2[O:25][CH:8]=[N:7][C:4]=2[CH3:5])=[N:30][NH:29][C:28]1=[S:31]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CNC(=S)NN
Reactant: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ncoc1-c1n[nH]c(=S)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
This material (498 g, 1 wt) was dissolved in dry tetrahydrofuran (5 vol), under nitrogen, cooled to 0° C. DCC (1.62 wt, 1 eq) was added portionwise followed by HOBt (1.07 wt, 1 eq). The mixture was warmed to 25±2° C. and stirred for 30 min. 4-Methyl-3-thiosemicarbazide (0.83 wt, 1 eq) was then added and the mixture further stirred for 2 h at 25±2° C. The mixture was filtered and the cake was washed with fresh tetrahydrofuran (1 vol) and dried on the filter for a few hours. The cake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70° C. for 30 min. After this time, the mixture was cooled to 25±2° C. and a solid was removed by filtration. The cake was washed with 1 M aqueous NaOH (10 vol). The combined mother liquors were cooled to 0° C. and acidified to ca. pH with HCl (aqueous, 16%; NOTE: keep temperature while adding HCl below +10° C.). The suspended product was isolated by filtration washing with water (2×3 vol). The cake was dried at 40° C. for 18 h in high vacuum to obtain 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 37%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24].C(N(CC)CC)C.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.[O:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:33]1([C:36]([O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][S:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([O:1][C:43]([CH:42]4[CH2:40][CH2:41]4)=[O:39])=[C:3]([N+:23]([O-:25])=[O:24])[CH:4]=3)(=[O:11])=[O:10])=[CH:14][C:15]=2[N+:20]([O-:22])=[O:21])=[O:37])[CH2:35][CH2:34]1
Reactant: O=[N+]([O-])c1cc(CS(=O)(=O)Cc2ccc(O)c([N+](=O)[O-])c2)ccc1O
Reactant: C1CCOC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(CS(=O)(=O)Cc2ccc(OC(=O)C3CC3)c([N+](=O)[O-])c2)cc1[N+](=O)[O-])C1CC1
Reaction time: 3 h

Procedure:
32.6 g of 4-hydroxy-3-nitrophenylmethylsulfone are suspended in 250 ml of tetrahydrofurane and to this suspension are added 21 ml of triethylamine. With stirring, 15.7 g of cyclopropanecarboxylic acid chloride are added dropwise to the resultant solution. After the weakly exothermic reaction has subsided, stirring is continued for 3 hours at room temperature and the filtrate is concentrated, affording 42 g of a viscous oil which is digested with petroleum ether. Yield: 40.5 g of pale yellow crystalline product with a melting point of 114°-116° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.C(O)(=O)C.[N:15]([O-])=[O:16].[Na+]>O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[N:15]=[O:16]
Reactant: CSc1cc(N)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(N)nc(N)c1N=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 6-Methylthio-pyrimidine-2,4-diamine (50.0 g; 321 mmol) in water (1000 mL) was added 500 mL of 2N acetic acid. The mixture was warmed to 50° C. and NaNO2 solution was added (24.0 g; 353 mmol in 200 mL H2O) rapidly. After 1 hr at 50° C., the deep Blue/purple mixture was allowed to cool to room temperature and filtered. The blue/purple solid was washed several times with water and finally washed with ether. The solid was allowed to air dry to give 51.0 g of 6-Methylthio-5-nitroso-pyrimidine-2,4-diamine 2 as blue/purple solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[CH2:12]1)[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:37])[CH3:36].[CH3:44][NH:45][SH:46](=[O:48])=[O:47].C1C2C(=CC=CC=2)CC1>FC(C1C=CC=CC=1)(F)F.[H-].[Na+]>[C:1]([O:5][C:6](=[O:21])[N:7]([C@@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:45]([S:46]([C:41]3[CH:42]=[CH:43][C:38]([CH:35]([CH3:37])[CH3:36])=[CH:39][CH:40]=3)(=[O:48])=[O:47])[CH3:44])[CH:17]=2)[CH2:12]1)[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN[SH](=O)=O
Reactant: CCCN(C(=O)OC(C)(C)C)[C@H]1Cc2ccc(Br)cc2C1
Reactant: CC(C)c1ccccc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: c1ccc2c(c1)CCC2
Solvent: FC(F)(F)c1ccccc1
Product: CCCN(C(=O)OC(C)(C)C)[C@H]1Cc2ccc(N(C)S(=O)(=O)c3ccc(C(C)C)cc3)cc2C1
Temperature: 150 °C
Reaction time: 1 h
Yield: 302.2 %

Procedure:
0.68 mmol of ((S)-5-Bromo-indan-2-yl)-propyl-carbamic acid tert-butyl ester were dissolved in 2.5 ml of trifluoromethylbenzene. 0.077 mg of tris(dibenzylidenaceton)-dipalladium(0) (0.08 mmol) and 0.068 mg of tritert.butylphosphine (0.34 mmol) were added. 0.362 mg of 4-isopropyl-benzene-N-methyl-sulfonamide (1.7 mmol) dissolved in 2.5 ml of trifluoromethylbenzene were treated with 0.068 mg of sodium hydride (60% in mineral oil), and the resulting suspension added to the indane solution. The reaction mixture was stirred at 150° C. for 1 h in the microwave (CEM), the solvent evaporated under reduced pressure, water added and the aqueous phase extracted twice with diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent evaporated to yield 1 g of a brownish oil that was further purified via silica gel chromatography using cyclohexane/ethyl acetate 7.5% as eluent. Fractions containing the product were combined and the solvent evaporated to yield 0.197 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:21]
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a solution of 2-chlorophenol (2.06 mL, 19.9 mmol) in DMF (40 mL) is added potassium carbonate (3.03 g, 21.9 mmol) and ethyl bromoacetate (2.3 mL, 20.7 mmol), and the mixture is stirred at 80° C. for 18 h. Et2O is added, and the mixture is washed with water, brine, dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is purified by chromatography in silica gel; elution with EtOAc: dichloromethane:hexane (10:5:85) gives 4.17 g of the product 465. 1H NMR (CDCl3) δ 7.38 (d, 1H), 7.21 (t, 1H), 6.92 (t, 1H), 6.84 (d, 1H), 4.70 (s, 2H), 4.27 (q, 2H), 1.29 (t, 3H); MS: m/z 215, 217 (M++1).