Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[N:10]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]>C1COCC1.CCCCCC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]([C:14]1[C:9]([Cl:8])=[N:10][C:11]([Cl:15])=[CH:12][CH:13]=1)=[O:21]
Reactant: Clc1cccc(Cl)n1
Reactant: O=Cc1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(c1cccc(Cl)c1)c1ccc(Cl)nc1Cl

Procedure:
A THF solution of diisopropylamine was treated with 1.6M butyl]ithium/hexane solution. Thereafter, 2,6-dichloropyridine was added dropwise thereto together with THF and reacted, and then 3-chlorobenzaldehyde was further added dropwise. The reaction mixture was worked up and purified in a usual manner and the resulting compound was reacted with manganese dioxide in toluene under heating. The reaction mixture was worked up and purified in a usual manner to obtain 3-(3-chlorobenzoyl)-2,6-dichloropyridine. MS: 286.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH:15]=O)=O)=[CH:9][CH:8]=1.[BH4-].[Na+]>CO.O1CCCC1>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][NH:4][CH2:1][CH2:2][NH:3]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C(=O)C=O)cc1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2CNCCN2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
Methanol (5 ml) solution of ethylenediamine (3.74 g, 62.29 mmol) was added to the ice-cooled solution of 4-methoxyphenylglyoxal (8.30 g, 45.5 mmol) in methanol (100 ml) and tetrahydrofuran (50 ml) and stirred for 10 min. After cooling to 0° C., sodium tetrahydroborate (6.14 g, 162.2 mmol) and additional methanol (50 ml) was added and stirred overnight. After removal of the solvent, aqueous sodium hydroxide was added and was extracted with dichloromethane three times and washed with brine and dried over sodium sulfate. After removal of the solvent, purification of the residue by silica gel column chromatography (eluent; dichloromethane/ethanol/diethylamine=20/2/1) gave 2-(4-methoxypheny)-piperazine (3.96 g, 45%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.O.[SH2:17].[Na]>CO>[SH:17][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)n2nc(C)nc2n1
Reactant: S
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(S)n2nc(C)nc2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
Methyl 7-chloro-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate (0.80 g) (3.53 mmol) are suspended in 35 ml of methanol and treated with 0.78 g (10.6 mmol) of sodium hydrogen sulphide hydrate. After stirring at 60° C. for 5 hours the mixture is concentrated and the residue is dissolved in 20 ml of water. The solution is acidified to pH 3 with 3N aqueous hydrochloric acid. The separated product is filtered off under suction and washed with water and methanol. After recrystallization from methanol/dichloromethane there is obtained 0.66 g of methyl 7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate as yellow crystals of melting point 237° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:9]([C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[CH:10][NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[Cl:24]C1C2C(=CC([N+]([O-])=O)=CC=2)N=CC=1C(OCC)=O.ClC1C=CC(NN)=CC=1>>[Cl:24][C:20]1[CH:21]=[CH:22][C:17]([N:15]2[C:14](=[O:23])[C:9]3=[CH:10][NH:11][C:12]4[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=4[C:8]3=[N:16]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1Cl
Reactant: O=c1c2c[nH]c3cc([N+](=O)[O-])ccc3c-2nn1-c1ccccc1
Agent: NNc1ccc(Cl)cc1
Product: O=c1c2c[nH]c3cc([N+](=O)[O-])ccc3c-2nn1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared following the procedure described for 12a using 11a and 4-chlorophenylhydrazine. 1H-NMR (DMSO-d6) δ (ppm): 7.48 (2H, d, m), 8.20 (2H, m), 8.26 (1H, dd, J=8.61, 2.08 Hz), 8.40 (1H, d, J=8.61 Hz), 8.52 (1H, d, J=2.08 Hz), 8.92 (1H, s). m/z 341.8 (MH+).
Reaction SMILES: [Si]([O:8][C@H:9]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:61]=[CH:60][C:34]([O:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH:43][C@@H:44]([C:57]([OH:59])=[O:58])[CH2:45][CH2:46][CH2:47][CH2:48][NH:49]C(OC(C)(C)C)=O)=[O:42])=[O:38])=[CH:33][CH:32]=1)(C(C)(C)C)(C)C.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Ce+4].[N+]([O-])(O)=O.O>CC#N>[F:68][C:65]1[CH:66]=[CH:67][C:62]([C@@H:9]([OH:8])[CH2:10][S:11][C@H:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:21][CH:22]=3)[C@@H:13]2[C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH:43][C@@H:44]([C:57]([OH:59])=[O:58])[CH2:45][CH2:46][CH2:47][CH2:48][NH2:49])=[O:42])=[O:38])=[CH:60][CH:61]=2)=[CH:63][CH:64]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCNS(C)(=O)=O)cc2)cc1)C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)NCC#Cc1ccc(N2C(=O)[C@H](SC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](CCCCN)C(=O)O)cc2)cc1
Temperature: 45 °C

Procedure:
N-({4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-N6-(tert-butoxycarbonyl)-D-lysine (Method 2) (21.9, 0.022 mmol) was dissolved in MeCN (1.5 ml). Cerium(4+) tetranitrate-nitric acid (1:2) diammoniate (25.1 mg, 0.046 mmol) and water (50 μl) were added. The reaction mixture was heated at 45° C. for 6 h and 30 minutes and it was allowed to stand at room temperature over the weekend. The solution was purified with preparative HPLC on a C8 column, UV 235/285 nm. A gradient from 10 to 90% MeCN in 0.1M NH4OAc buffer was used as eluent. Most of the MeCN was removed under reduced pressure and the residue was lyophilised to give the title compound as a yellow solid. H-NMR (500 MHz, DMSO-d6): 1.13-1.66 (m, 6H), 2.64-2.71 (m, 2H), 2.90-2.96 (m, 2H), 2.97 (s, 3H), 3.62-3.80 (m, 3H), 4.00 (s, 2H), 4.34 (d, 1H), 4.53 (s, 2H), 4.72 (t, 1H), 5.09 (d, 1H), 6.99 (d, 2H), 7.07-7.13 (m, 2H), 7.20 (d, 2H), 7.32-7.40 (m, 6H), 7.46 (b, 1H), 8.42 (t, 1H). M/z: 782.58 (M−1) and 784.42 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][F:39]>CC(C)=O>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([CH2:37][CH2:38][F:39])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(CCF)C2
Temperature: 50 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a suspension of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (98.4 mg, 0.244 mmol) and K2CO3 (135 mg, 0.976 mmol) in acetone (4.0 mL) was added 1-bromo-2-fluoroethane (0.020 mL, 0.268 mmol) at 23° C. The reaction mixture was stirred at 50° C. for 1 hr. The reaction mixture was cooled to 23° C., an additional portion of 1-bromo-2-fluoroethane (8.2 μL, 0.110 mmol) was added, and the reaction mixture was heated for an additional 1.5 hr at 50° C., cooled to 23° C., and concentrated via rotary evaporation. The resulting crude material was reconstituted in DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B using a 30% to 70% ACN gradient to give the title compound (42 mg, 38.3%) as a light yellow oil. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.17 (d, J=6.8 Hz, 6H), 1.82-1.93 (m, 2H), 2.02-2.11 (m, 2H), 2.62-2.69 (m, 2H), 2.73-2.80 (m, 3H), 2.81-2.91 (m, 3H), 3.20-3.29 (m, 2H), 3.48 (s, 2H), 4.04-4.12 (m, 1H), 4.47-4.54 (m, 1H), 4.56 (t, J=4.9 Hz, 1H), 4.66 (t, J=4.9 Hz, 1H), 5.38 (d, J=7.8 Hz, 1H), 6.98-7.05 (m, 1H), 7.26-7.34 (m, 2H); ESI-MS m/z [M+H]+ 450.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@@:24]1([CH2:28][N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[C@H:26](C)[O:25]1.[C:34](OCC)(=O)C>CN(C)C=O>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@@:24]([OH:25])([C@:28]([N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)([S:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[CH3:34])[CH3:26]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(S[C@@](C)(n2cncn2)[C@](C)(O)c2ccc(F)cc2F)CC1
Reaction time: 0.33 h
Yield: 53 %

Procedure:
In 6 ml of dimethylformamide was dissolved 1-(tert-butoxycarbonyl)-4-mercaptopiperidine (corresponding to 2 mmol) as described in Reference example 12, and 86 mg (1.97 mmol) of 55% sodium hybride were added to the solution at 0° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at the same temperature for 20 minutes. Then, 503 mg (2.00 mmol) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane were added to the reaction mixture and the mixture was stirred at 60° C. for 3 hours. After cooling, ethyl acetate was added to the reaction mixture to dilute it and washed successively with water and a saturated aqueous NaCl solution. An oil obtained by evaporation of the solvent was subjected to silica gel column chromatography and eluted with ethyl acetate to obtain 557 mg (yield: 53%) of the desired compound as an oil.
Reaction SMILES: [C:1]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[C:11]([CH3:16])[CH:10]=[CH:9][N:8]=1)(=O)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.C(O)C.[Fe]>[CH3:16][C:11]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:6][C:1]([CH2:2][CH2:3][CH3:4])=[N:13][C:12]=12
Reactant: CCCC(=O)Nc1nccc(C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1nc2c(C)ccnc2[nH]1
Temperature: 90 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
A solution of 2-butyrylamino-4-methyl-3-nitropyridine (7.0 g) and iron powder (17.5 g) in a mixture of acetic acid (14 ml) and ethanol (100 ml) was stirred at 90° C. for 3 hours under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was filtered through Celite and the filtrate was evaporated in vacuo. Ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the residue until pH 7-8 and the resulting suspension was filtered through Celite. The organic layer of the filtrate was separated, washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified with silica gel column chromatography (eluent:ethyl acetate) to give 7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (3.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([OH:11])[OH:10])=[CH:4][C:3]=1[F:13].F[C:15]1C=C(C2C=NC3N(C(CC4C=C5C(=CC=4)N=CC=C5)=CN=3)N=2)C=C[C:16]=1C(NC[C@H](O)C)=O.C([O-])([O-])O[CH2:50][CH3:51].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([O:10][CH2:50][CH3:51])[O:11][CH2:15][CH3:16])=[CH:4][C:3]=1[F:13]
Reactant: O=C(c1ccc(Br)c(F)c1)C(O)O
Reactant: C[C@@H](O)CNC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
To a mixture of 1-(4-bromo-3-fluorophenyl)-2,2-dihydroxyethanone and 4-bromo-3-fluorophenyl)(oxo)acetaldehyde (crude product from Step 3, 7.0 g, 28 mmol) in toluene (50 mL) was added ethyl orthoformate (12 mL, 70 mmol) and p-toluenesulfonic acid (200 mg, 1 mmol). The reaction mixture was refluxed for 4 h. The reaction mixture was cooled to RT, diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water, brine, and dried over magnesium sulfate. Concentration under reduced pressure gave the desired product which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])/[CH:14]=[C:15](/[O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[F:1])\[CH3:16])[CH3:11]
Reactant: Cc1cccc(O)c1F
Reactant: CC#CC(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(C)c1F
Yield: 22.3 %

Procedure:
To a stirred mixture of 2-fluoro-3-methyl-phenol (20.0 g, 0.158 mol) and ethyl-2-butynoate (33.6 g, 0.300 mol) in tetrahydrofuran (100 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (25.4 g, 0.167 mol) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 330 g, 0% to 15% ethyl acetate/hexanes) which afforded (E)-3-(2-fluoro-3-methyl-phenoxy)-but-2-enoic acid ethyl ester (8.40 g, 23%) as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][CH:7]=1)=[O:5])[CH3:2].C(OC(=O)C)(=O)C.C(O)(=O)C.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[CH:35]=O>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:35]/[C:25]2[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:27][O:28][C:24]=2[CH3:23])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(C)s1
Reactant: Cc1onc(-c2ccccc2)c1C=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnc(/C=C/c2c(-c3ccccc3)noc2C)s1
Temperature: 120 °C
Reaction time: 144 h
Yield: 19.2 %

Procedure:
2-Methyl-thiazole-5-carboxylic acid ethyl ester (547 mg, 2.92 mmol) was dissolved in acetic anhydride (0.15 mL, 15.5 mmol) and acetic acid (0.04 mL, 2.54 mmol) then 5-methyl-3-phenyl-4-isoxazolecarbaldehyde (500 mg, 2.92 mmol) was added and the reaction mixture warmed to 120° C. After 6 days, the reaction mixture was cooled to room temperature then diluted with water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 0 to 30% ethyl acetate in heptane) to give the title compound (191 mg, 19%) as an off-white solid after trituration with isopropylether. MS: m/e=341.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([N+:16]([O-:18])=[O:17])[C:12]([CH3:19])=[N:11]1.[Br-].[C:21](=O)([O-])[O-].[K+].[K+].[C:27](#N)[CH3:28]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:21][C:27]#[CH:28])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([N+:16]([O-:18])=[O:17])[C:12]([CH3:19])=[N:11]1
Reactant: O=C([O-])[O-]
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(C)c1[N+](=O)[O-]
Reactant: CC#N
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#CCOc1cc(-n2nc(C)c([N+](=O)[O-])c2C)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,5-dimethyl-4-nitropyrazole (28.7 g), propargy bromide (13.1 g), anhydrous potassium carbonate (15.2 g) and acetonitrile (200 ml) was stirred at 60° C. for 2 hours. After cooling, the reaction mixture was filtered through a filter to remove crystalline solid matters and the filtrate was concentrated to a small volume under reduced pressure. The concentrated solution was admixed with toluene and water to form two layers. The toluene layer formed (the extract) was separated, washed with water and then dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (31.2 g) as a pale yellow crystalline solid. Recrystallization of this solid from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 125°-126.5° C.
Reaction SMILES: [OH-:1].[K+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.O>O>[CH:6]12[CH2:7][CH:4]([CH:4]=[CH:5]1)[CH2:5][CH:6]2[C:7]([OH:3])=[O:1]
Reactant: C1CCOC1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
27.5 g (110 mmol) of the Diels-Alder adduct obtained in the above step was dissolved in 420 ml of a mixture solvent of tetrahydrofuran-water (5:2), on ice cooling, 30.0 g (455 mmol) of potassium hydroxide (85%) in 120 ml of water was added, and the mixture was stirred at room temperature for 24 hours. After distilling off tetrahydrofuran, the residue was neutralized with 40 ml of concentrated hydrochloric acid, and the solution was extracted with a mixture solvent of hexane-methylene chloride (98:2) (150 ml×4). The extract was dried over anhydrous magnesium sulfate and filtered, the solvent was distilled off, and 15.7 g of crude 5-norbornene-2-carboxylic acid was obtained. Crude yield: 100%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([OH:9])[CH3:8].Cl[C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.[CH3:18][C:19]1([CH3:28])[CH2:24][CH:23]([NH2:25])[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1>>[CH3:18][C:19]1([CH3:28])[CH2:24][CH:23]([NH:25][C:11]2[N:16]=[C:15]([C:5]3[S:1][C:2]([CH2:6][CH:7]([OH:9])[CH3:8])=[CH:3][CH:4]=3)[CH:14]=[CH:13][N:12]=2)[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(O)Cc1cccs1
Product: CC(O)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Steps B and C of Method A, starting from 1-thiophen-2-yl-propan-2-ol, 2,4-dichloro-pyrimidine and 2,2,6,6-tetramethyl-piperidin-4-ylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:17]=1.C[Si]([N:22]=[C:23]=[N:24][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]/[C:7](=[N:24]\[C:23]#[N:22])/[C:6]=2[CH:17]=1
Reactant: O=C1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a solution of 8-chlorodibenzo[b,f]oxepin-10(11H)-one (732 mg, 3.84 mmol) in anhydrous DCM (30 mL) was added TiCl4 (1 M solution in DCM, 7.8 mL, 7.8 mmol) dropwise within 15 minutes at room temperature. It was stirred another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (1.48 g, 1.89 mL, 8.46 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (100 g), extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(8-chlorodibenzo[b,f]oxepin-10(11H)-ylidene)cyanamide (500 mg, 68%), which was used for next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[F:31].[CH3:32][PH:33](=[O:35])[CH3:34]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([P:33]([CH3:34])([CH3:32])=[O:35])=[C:23]([F:31])[CH:24]=2)[CH:3]=1)[CH3:11]
Reactant: C[PH](C)=O
Reactant: OB(O)c1ccc(Br)c(F)c1
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)c(F)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromo-3-fluoro-phenyl boronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 471 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:25]O>>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:25])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoic acid (25.63 g, 70.69 mmol) in MeOH (300 mL) was added thionyl chloride (20 mL). The resulting solution was stirred at 85° C. overnight. Most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v), the corresponding product was obtained as a white solid (22.84 g, 85.8% yield). 1H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 8.06 (m, 1H), 7.41 (m, 1H), 7.24 (m, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [C:1]([N:4]([C:8]1[C:12]2[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].NC1C2C=C([N+]([O-])=O)C=CC=2SN=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C=O)C>[C:1]([N:4]([C:8]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1nsc2ccc([N+](=O)[O-])cc12
Agent: Nc1nsc2ccc([N+](=O)[O-])cc12
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N(C(C)=O)c1nsc2ccc(N)cc12
Reaction time: 4 h

Procedure:
N-acetyl-N-(5-nitro-benzo[d]isothiazol-3-yl)-acetamide (KRB01049): To a solution of 3-amino-5-nitrobenzisothiazole (1.00 g, 5.12 mmol) in DMF (20 mL) was added acetic anhydride (1 mL) and triethylamine (1 mL) and the resulting solution was stirred for 4 h. The yellow precipitate was filtered, washed quickly with cold ethyl acetate, and dried in vacuo (1.139 g, 80%). 1H NMR (CDCl3): δ 9.20 (1H, d, J=2.5 Hz), 8.87 (1H, d, J=9.4 Hz), 8.55 (1H, dd, J=9.4, 2.5 Hz), 2.69 (3H, s), 2.63 (3H, s).