Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=O.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10]>O.C(OC(C)C)(C)C>[S:10]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:1]1
Reactant: C=O
Reactant: Nc1ccccc1S
Solvent: CC(C)OC(C)C
Solvent: O
Product: c1ccc2c(c1)NCS2
Reaction time: 0.5 h

Procedure:
37% formalin (5.2 mL) was diluted with water (80 mL), and diisopropylether (80 mL) and 2-aminobenzenethiol (7.84 g) were added, and then the mixture was stirred at mom temperature for 30 minutes. The organic layer was separated and the aqueous layer was extracted with diisopropylether. The organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (c).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[C:13]=1[CH3:29]>N1C=CC=CC=1>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][O:18][C:14]2[C:13]([CH3:29])=[C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=2)=[CH:22][CH:23]=1)#[N:28]
Reactant: Cc1c(N)cccc1OCCc1ccc(C#N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1c(NS(=O)(=O)c2ccccc2)cccc1OCCc1ccc(C#N)cc1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Benzenesulfonyl chloride (0.24 mL; 1.9 mmol) was added to a stirred solution of amino-3-[2-(4-cyanophenyl)ethoxy]-2-methylbenzene (0.42 g ; 1.7 mmol; from step (iii) above) in dry pyridine (20 mL) under nitrogen. The reaction was left overnight at room temperature. After evaporation of the solvent the residue was partitioned between 10% aqueous HCl and EtOAc. The organic layer was washed with brine, dried (MgSO4) and the solvent removed in vacuo. Purification by flash chromatography afforded 0.47 g (72%) of the sub-title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH:21]=1)=[O:4].Cl.N1C=CC=CC=1>O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:21][C:9]=3[CH:10]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc2oc(-c3ccc(OC)cc3)cc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc2oc(-c3ccc(O)cc3)cc2c1
Temperature: 200 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
A mixture of 142 (0.45 g, 1.6 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried, concentrated to give a solid which was triturated. with CH2Cl2 and filtered to give 143 (0.23 g, 58%): Mp>300° C.; 1H NMR (DMSO-d6) δ 12.87 (br s, 1 H), 9.86 (br s, 1 H), 8.21 (d, 1 H, J=1.6 Hz), 7.86 (dd, 1 H, J=8.8 Hz, 1.5 Hz), 7.76 (d, 2 H, J=8.8 Hz), 7.67 (d, 1 H, J=8.8 Hz), 7.29 (s, 1 H), 6.89 (dd, 2 H, J=7.7 Hz, 2.0 Hz); MS 253 (M−H)−
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: Sc1ccccn1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3ccccn3)C(=O)O)cc2)cc1

Procedure:
Example 47 is prepared from 2-mercaptopyridine and 1d using the procedure described for compound 20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][O:15][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cccc(CO)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2cccc(COS(C)(=O)=O)c2)cc1
Reaction time: 19 h
Yield: 89 %

Procedure:
To a solution of the obtained (3-(4-methoxy-phenoxy)-phenyl)-metanol (2.0 g, 8.73 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.81 mL, 10.5 mmol) and triethylamine (1.46 mL, 10.5 mmol) on an ice bath, and the solution was stirred for 19 hours. The reaction solution was diluted with dichloromethane, washed with an aqueous solution of 5% sodium bicarbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain methanesulfonic acid 3-(4-methoxy-phenoxy)benzyl ester (2.49, 89%) as a pale brown oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[N:10]([CH:13]1[CH2:15][CH2:14]1)=[C:11]=[S:12]>CC(O)C>[CH:13]1([N:10]2[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8][NH:9][C:11]2=[S:12])[CH2:15][CH2:14]1
Reactant: S=C=NC1CC1
Reactant: NNC(=O)c1cccs1
Solvent: CC(C)O
Product: S=c1[nH]nc(-c2cccs2)n1C1CC1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a slurry of thiophene-2-carboxylic acid hydrazide (866 mg, 6.09 mmol) in iPrOH (25 ml) was added isothiocyanato-cyclopropane (602 mg, 6.08 mmol). The mixture was stirred at 70° C. for 72 h and then cooled to room temperature. The white precipitate was filtered off and suspended in a MeOH:H2O (9:1, 40 ml) together with aq. NaOH (2%, 5 ml). The reaction mixture was stirred at 70° C. overnight and then cooled to room temperature. The pH was adjusted to around 4 with aq. HCl (1N). The formed white precipitate was filtered off, washed with water and dried under vacuum (829 mg, 61%). 1H NMR (CD3OD), δ (ppm): 7.67 (dd, 1H), 7.63 (dd, 1H), 7.17 (dd, 1H), 3.15 (m, 1H), 1.14 (m, 2H), 0.86 (m, 2H).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1.C(O)(=O)C>C(O)C.[OH-].[Na+]>[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3F)ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)c(F)c1

Procedure:
1.2 g (2.75 mmol) of the ester from Example 69 were stirred overnight at room temperature in a mixture of 20 ml ethanol and 5 ml 2 N aqueous sodium hydroxide solution. It was brought to pH 4 with 2 N acetic acid, and the precipitate of the title compound was filtered with suction, washed successively with water and with acetone, and dried in vacuo at 50° C. Yield: 0.84 g (82%) of a pale yellow powder, m.p. 250° C.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.[CH3:21][C:22]([CH3:33])([C:28](OCC)=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH2:26]([O:25][C:23](=[O:24])[C:22]([CH3:33])([CH3:21])[C:28]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:29])[CH3:27]
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
sec-Butyl lithium (5.85 mL, 7.6 mmol) was added to a solution of 1-bromo-4-benzyloxy-benzene (2.0 g, 7.6 mmol) in THF (10 mL) cooled to −78° C. under nitrogen. The reaction was stirred for 1 h and diethyl dimethylmalonate (4.29 g, 22.8 mmol) was added rapidly. This was stirred for an additional 0.5 h and then allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by flash column chromatography (FCC) on silica gel eluting hexane:ethyl acetate (90: 10, v:v) to give 3-(4-benzyloxy-phenyl)-2,2-dimethyl-3-oxo-propionic acid ethyl ester (1.25 g, 50%) as an oil. MS found: (M+H)+=327.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[O:17]([NH2:19])[CH3:18]>C(O)C.N1C=CC=CC=1>[CH3:18][O:17][N:19]=[C:6]([C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(c1ccccc1)c1ccc(Br)cc1
Yield: 93.1 %

Procedure:
A mixture of 4-bromobenzophenone (3.02 g, 0.0116 mol) and methoxylamine hydrochloride (4.83 g, 0.0578 mol) was heated in a mixture of ethanol (90 mL) and pyridine (18 mL) at reflux for 2 hours under an atmosphere of nitrogen. The solvents were removed under reduced pressure and the residue was partitioned between water (150 mL) and dichloromethane (100 mL). The water phase was further extracted twice with dichloromethane (80 mL each) and the combined organic extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using ethyl acetate/n-heptane (2:98) as mobile phase to yield (4-bromophenyl)(phenyl)methanone O-methyloxime as a colorless oil (3.13 g, 0.0108 mol): 1H NMR (DMSO-d6, 400 MHz) 7.67 (d, 1H), 7.59 (d, 1H), 7.48 (m, 4H), 7.32 (m, 1H), 7.26 (m, 2H), 3.93 (s, 3H) TLC (ethyl acetate/heptane 1:9) Rf 0.44.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1C
Yield: 13.4 %

Procedure:
As described for Example 9, 0.628 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.506 g (3.0 mmol) of 2,3-dimethylbenzoyl chloride in dichloromethane. The product is recrystallized from hexane-dichloromethane to give 0.12 g of crystals, m.p. 138°-142° C. Anal. Calc'd for C30 H26N2O2 : C,80.7; H,5.9; N,6.3. Found: C,80.0; H,5.9; N,6.1.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([S:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[N:10][N:9]=[C:8]2[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.[C:24]1(=[O:34])[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>O1CCCC1>[CH2:18]([C:8]1[N:7]([CH2:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:24](=[O:34])[C:25]3[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=3[C:27]([OH:29])=[O:28])=[CH:3][CH:4]=2)[C:11]([S:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[N:10][N:9]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1nnc(SCC(=O)OC)n1Cc1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCCCc1nnc(SCC(=O)OC)n1Cc1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 566 mg (1.69 mmole) of 4-(4-aminobenzyl)-3-n-butyl-5-(carbomethoxymethylthio)-4H-1,2,4-triazole in 15 ml of dry tetrahydrofuran (THF) was treated with 250 mg (1.69 mmole) of phthalic anhydride dissolved in 2 ml of dry THF. The resulting solution was stirred overnight at room temperature in a stoppered flask. The solid which had precipitated was collected on a filter and washed with ether to yield (after vacuum-drying at 30° C.) 629 mg (77%) of a white solid, mp 161°-162° C., homogeneous by TLC in 90:10:1CH2Cl2 --MeOH-AcOH; mass spectrum (FAB) m/e 483 (M+1)+.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][C:8]=1[C:15]#[N:16].[F:17][C:18]([F:26])([F:25])[C:19](=O)[CH2:20][C:21](=O)[CH3:22]>C(O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21]([CH3:22])=[CH:20][C:19]([C:18]([F:26])([F:25])[F:17])=[N:14]2)=[CH:9][C:8]=1[C:15]#[N:16]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: N#Cc1cc(NN)ccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1-c1ccc(F)c(C#N)c1
Yield: 55.4 %

Procedure:
To a suspension of 4-fluoro-3-cyanophenylhydrazine tin chloride (20 g, 53.6 mmol) in ethanol (150 mL) was added 1,1,1-trifluoro-2,4-pentanedione (8.18 g, 53.6 mmol). The reaction was brought to reflux overnight. The next day the ethanol was evaporated and the residue partitioned between ethyl acetate and HCl (1 N). The aqueous phase was extracted with ethyl acetate (4×20 mL). The organic phase is washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography gave 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-methylpyrazole (8 g, 56% yield) as pure compound: MS (CI): 270 (M+H)+ (100%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C@@H:19]1[CH2:28][CH2:27][C@@H:26]([OH:29])[C:22]2[N:23]=[CH:24][S:25][C:21]=2[C@H:20]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].N1([C:43]([N:45]2[CH2:50][CH2:49][CH:48]([N:51]3[C:59]4[C:54](=[N:55][CH:56]=[CH:57][CH:58]=4)[NH:53][C:52]3=[O:60])[CH2:47][CH2:46]2)=[O:44])C=CN=C1>CN(C)C=O>[O:60]=[C:52]1[NH:53][C:54]2=[N:55][CH:56]=[CH:57][CH:58]=[C:59]2[N:51]1[CH:48]1[CH2:47][CH2:46][N:45]([C:43]([O:29][C@H:26]2[C:22]3[N:23]=[CH:24][S:25][C:21]=3[C@@H:20]([NH:30][C:31]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:37])[C@H:19]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=3[F:11])[CH2:28][CH2:27]2)=[O:44])[CH2:50][CH2:49]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2scnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Reactant: O=C(N1CCC(n2c(=O)[nH]c3ncccc32)CC1)n1ccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1c2scnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
NaHMDS (0.228 mL, 0.228 mmol) was added to a dimethylformamide (1 mL) solution of tert-butyl (4R,7S,8S)-7-(2,3-difluorophenyl)-4-hydroxy-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-8-ylcarbamate (20.1 mg, 0.051 mmol) and 1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (23.7 mg, 0.076 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h and rt for 2 h before quenching with water. The reaction was diluted with ethyl acetate and the organic layer was separated, washed with water and brine and then dried (sodium sulfate), filtered and concentrated. Flash chromatography, eluting with methanol in methylene chloride from 0 to 10% gave the desired product (18.2 mg, 56%): LCMS (M+H=641.38); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.64 (1H, s), 8.07 (1H, d, J=5.0 Hz), 7.31-7.56 (1H, m), 6.93-7.12 (4H, m), 6.22 (1H, d, J=7.5 Hz), 5.24-5.34 (1H, m), 4.96-5.07 (1H, m), 4.32-4.71 (3H, m), 3.61-3.77 (1H, m), 2.88-3.15 (2H, m), 2.29 (4H, d, J=10.5 Hz), 1.83-1.97 (4H, m), 1.30 (9H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10](O)[CH:11]=1)=[O:5])[CH3:2].P(Br)(Br)([Br:19])=O.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Br:19])[CH:11]=1)=[O:5])[CH3:2]
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)c1cc(O)nc2[nH]nc(C)c12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(Br)nc2[nH]nc(C)c12
Temperature: 110 °C
Reaction time: 5 h
Yield: 26.1 %

Procedure:
A mixture of 6-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (13.7 g) and phosphorous oxybromide (19.5 g) in toluene (300 mL) was stirred at 110° C. for 5 h, cooled to r.t., and added dropwise into an ice cold solution of potassium acetate (18.2 g) in water (300 mL). The mixture was extracted twice with ethyl acetate, the combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in a membrane pump vacuum. 6-Bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (4.6 g, 26% yield) was obtained. This material was dissolved in THF (60 mL), and 3,4-dihydro-2H-pyran (1.6 mL) and p-toluenesulfonic acid monohydrate (0.91 g) was added. The solution was stirred at r.t. for 48 h, then 3,4-dihydro-2H-pyran (1.6 mL) was added and the solution stirred again for 48 h. The mixture was poured into water and extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated in a membrane pump vacuum. The residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient). 6-Bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (2.2 g, 38%) was obtained.
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1)=O)C>O.C(O)C>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1
Reactant: CCOC(=O)N1CCOC(C=C2c3ccccc3CCc3ccccc32)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1

Procedure:
Potassium hydroxide (3.0 g) in water was added to the above-obtained 5-(4-ethoxycarbonylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.49 g) in ethanol, and the resulting mixture was heated under reflux for 8 hours. After cooling, ethanol was distilled off and water was added to the resulting residue. The resultant mixture was extracted with chloroform. The chloroform extract was dried, evaporated and chromatographed to afford 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 221°-224° C. (oxalate).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N:6]1([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][NH:24][C:25](=[O:31])[CH2:26][S:27][CH2:28][CH2:29][OH:30])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[N:6]1([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][NH:24][C:25](=[O:31])[CH2:26][S:27][CH2:28][CH2:29][O:30][C:1](=[O:4])[CH2:2][CH3:3])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCC(=O)Cl
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
0.09 ml of propionyl chloride was added to a mixture of 0.40 g of N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 1.02 ml of pyridine, and the resulting mixture was allowed to stand at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into ice-water, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting mixture, after which it was extracted with chloroform. The extract was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.39 g (yield 85%) of the title compound as an oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21]([O:23]CC)=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O1CCOCC1>O>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21]([OH:23])=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3cc(C(=O)O)n[nH]3)c2nc1NC(C)(C)C
Temperature: 100 °C

Procedure:
To a 10-mL reaction vial was added ethyl 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylate (467a) (94 mg, 0.27 mmol), LiOH hydrated (56 mg, 1.33 mmol), dioxane (4 mL), and water (1 mL). The reaction mixture was heated at 50° C. for 1 h and at 100° C. for 2 h and then cooled to RT. The solvent was removed under vacuum and HCl (1N, 3 mL) was added, the yellow precipitate obtained was filtered off, washed with water, and dried. 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylic acid (467b) was obtained as a yellow solid and used without further purification. To a 50-mL round-bottomed flask was added 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylic acid (467b) (77 mg, 0.24 mmol), DCM (3 mL), DMF (1 mL), DIPEA (82 μL, 0.47 mmol), ammonia (0.95 mL, 0.47 mmol, 0.5 M in dioxane), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (123 mg, 0.24 mmol) (Sigma-Aldrich). The reaction mixture was stirred at RT for 30 min, concentrated to half of its volume, and diluted with EtOAc (20 mL). The organic extract was washed with sat NaHCO3 (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 40% EtOAc in hexanes to give 5-(3-(tert-butylamino)-2-methyl-quinoxalin-5-yl)-1H-pyrazole-3-carboxamide (467) (65 mg, 85% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br. s, 1H), 7.85 (dd, J=1.08, 7.34 Hz, 1H), 7.76 (d, J=7.63 Hz, 1H), 7.53 (br. s., 1H), 7.41 (t, J=7.73 Hz, 1H), 7.30 (s, 1H), 7.18 (br. s, 1H), 6.06 (br. s., 1H), 2.58 (s, 3H), 1.52 (s, 9H). m/z (ESI, +ve) 325.1 (M+H)+.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH3:12].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:12][C:11]1[N:10]=[CH:9][N:8]2[C:7]=1[CH:6]=[N:5][NH:4][C:3]2=[S:2]
Reactant: CSC(=S)NN=Cc1nc[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ncn2c(=S)[nH]ncc12

Procedure:
A suspension of 14.39 gm. of 3-(5-methyl-4-imidazolylmethylene)dithiocarbazic acid methyl ester in 100 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product as yellow crystals, m.p. 262°-268° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]([CH3:11])[C:4]=1[CH3:12])=[O:2].[CH2:13]([C:15]1[CH:30]=[C:29]([C:31](=[NH:34])[NH:32]O)[CH:28]=[C:27]([CH3:35])[C:16]=1[O:17][CH2:18][C@@H:19]([OH:26])[CH2:20][NH:21][C:22](=[O:25])[CH2:23][OH:24])[CH3:14]>>[CH2:13]([C:15]1[CH:30]=[C:29]([C:31]2[N:34]=[C:8]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:12])[C:5]=3[CH3:11])[O:10][N:32]=2)[CH:28]=[C:27]([CH3:35])[C:16]=1[O:17][CH2:18][C@@H:19]([OH:26])[CH2:20][NH:21][C:22](=[O:25])[CH2:23][OH:24])[CH3:14]
Reactant: Cc1c(C=O)sc(C(=O)O)c1C
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: CCc1cc(-c2noc(-c3sc(C=O)c(C)c3C)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-3,4-dimethyl-thiophene-2-carboxylic acid and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide; LC-MS: tR=0.95 min; [M+H]+=474.07; 1H NMR (D6-DMSO): δ 1.22 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 2.57 (s, 3H), 2.63 (s, 3H), 2.73 (q, J=7.8 Hz, 2H), 3.20-3.28 (m, 1H), 3.39-3.48 (m, 1H), 3.70-3.81 (m, 2H), 3.84 (d, J=5.5 Hz, 2H), 3.92-4.01 (m, 1H), 5.31 (d, J=4.8 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.70 (t, J=5.3 Hz, 1H), 7.77 (s, 2H), 10.22 (s, 1H).