Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[C:18]([CH2:28][PH:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:47])([F:46])[CH2:38][S:39]([CH2:42][C:43](O)=[O:44])(=[O:41])=[O:40].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@@H:15]([NH:16][C:43](=[O:44])[CH2:42][S:39]([CH2:38][C:37]([F:46])([F:36])[F:47])(=[O:40])=[O:41])[C@H:12]2[S:11][CH2:10][C:9]=1[C:18]([CH2:28][PH:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Reactant: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)CS(=O)(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 12 h

Procedure:
To a solution of 10.42 g (0.019 mol) of 7-amino-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g (0.019 mol) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g (0.019 mol) of dicyclohexylcarbodiimide in 100 ml of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7β-(2,2,2-trifluoroethylsulfonylacetamido)-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](OC)=O)=[C:6]([CH3:12])[CH:5]=[C:4]([CH2:13][CH2:14][C:15]([OH:33])([CH3:32])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:31])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]=1[C:34](OC)=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1.C1C=CC=CC=1>[CH3:8][C:7]1[C:6]([CH3:12])=[CH:5][C:4]([CH2:13][CH2:14][C:15]([OH:33])([CH3:32])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:31])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])=[C:3]([CH3:34])[C:2]=1[OH:1]
Reactant: COC(=O)c1c(C)cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C(=O)OC)c1O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Product: Cc1cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C)c(O)c1C
Yield: 99.9 %

Procedure:
To a solution of the dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate (5.17 g) in xylene (25 ml) at 10° was added sodium dihydrobis(2-methoxyethoxy) aluminate (20 ml of a 70% by weight solution in benzene) over 20 min with occasional cooling to keep the temperature at 10°. After 10 min the solution was heated to reflux for 1.5 hr, cooled to 10° and was poured cautiously into cold 20% by weight aqueous sulfuric acid (200 ml). The mixture was extracted with ether (3× 100 ml) and the combined extracts were washed with aqueous sodium bicarbonate and brine and dried (Na2SO4) and concentrated on a rotary evaporator to give 4.29 g of crude 2,3,6-trimethyl-5-(3-hydroxy-3,7,11, 15-tetramethylhexadecanyl)-phenol as a light yellow oil. Chromatography on silica gel eluting with ether in petroleum ether gave 3.19 g of pure 2,3,6-trimethyl-5-(3-hydroxy-3,7,11,15-tetramethylhexadecanyl)-phenol.
Reaction SMILES: [CH:1]([C:4]1[C:13]([CH:14]([CH3:16])[CH3:15])=[N:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[OH2:17]>C(O)(=O)C>[CH:1]([C:4]1[C:13]([CH:14]([CH3:16])[CH3:15])=[N:12][C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:17])[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(nc1C(C)C)CCCC2
Reactant: O
Solvent: CC(=O)O
Product: CC(C)c1nc2c(nc1C(C)C)C(=O)CCC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1.5 g of 5,6,7,8-tetrahydro-2,3-diisopropylquinoxaline was dissolved in 10 ml of acetic acid, followed by the dropwise addition of a solution of 1.0 g of chromic acid anhydride in acetic acid (6 ml) /water (1 ml). The obtained mixture was stirred at 80° C. for 2 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 10% ethyl acetate/hexane) to give 0.6 g of the title compound as a brown solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].C(OC([N:37]1[C:45]2[C:40](=[CH:41][C:42]([CH:46]=O)=[CH:43][CH:44]=2)[CH:39]=[C:38]1[C:48]1[C:49](=[O:58])[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)=O)(C)(C)C>C1COCC1>[CH3:2][O:3][CH:4]=[CH:46][C:42]1[CH:41]=[C:40]2[C:45](=[CH:44][CH:43]=1)[NH:37][C:38]([C:48]1[C:49](=[O:58])[NH:50][C:51]3[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:39]2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3[nH]c2=O)cc2cc(C=O)ccc21
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (methoxymethyl)triphenylphosphonium chloride (3.6 g, 10.5 mmol, 2.1 equiv) and potassium t-butoxide (2.48 g, 22 mmol, 4.4 equiv) was stirred 1 hour at 25° C. before a suspension of t-butyl 5-formyl-2-(2-oxo-1,2-dihydroquinolin-3-yl)-1H-indole-1-carboxylate (5-8, 1.94 g, 5.0 mmol, 1 equiv) in THF (100 mL) was added via canula and the resulting mixture was stirred at 25° C. for 18 hours. The reaction was concentrated and the residue was stirred in saturated NH4Cl solution. The insoluble solid was collected by filtration and sonicated in EtOAc and then water to give 3-{5-[2-methoxyethenyl]-1H-indol-2-yl}quinolin-2(1H)-one (10-1) as a 1:1 mixture of E and Z isomers. MS(M+1)=317.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:17]4[C:24]5[CH2:25][NH:26][CH2:27][C:23]=5[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl.[CH3:32][N:33]([CH3:40])[CH2:34]/[CH:35]=[CH:36]/[C:37](O)=[O:38]>>[CH3:32][N:33]([CH3:40])[CH2:34]/[CH:35]=[CH:36]/[C:37]([N:26]1[CH2:27][C:23]2[S:22][C:18]3[N:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4[CH:10]=[C:9]5[C:14](=[CH:13][CH:12]=4)[N:6]([CH2:5][C:4]4[CH:28]=[CH:29][CH:30]=[C:2]([F:1])[CH:3]=4)[N:7]=[CH:8]5)[C:17]=3[C:24]=2[CH2:25]1)=[O:38]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CNC6)ccc32)c1
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 33A (51 mg, 0.12 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (29 mg, 0.17 mmol) to yield 30 mg (44%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18]([C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[NH2:23][C@H:20]([CH2:21][CH3:22])[C:18]([NH:17][C:14]1[CH:15]=[N:16][C:11]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)=[CH:12][CH:13]=1)=[O:19]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1,1-dimethylethyl ((1R)-1-{[(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 69, 1.28 g) was dissolved in 18 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (7.15 mL, 93 mmol). The reaction was stirred during 3 hours at 0° C. The reaction mixture was evaporated. The residue obtained was purified by SCX on a 50 g cartridge. The cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). After evaporation of the volatiles, the title compound was obtained (932 mg).
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:5])=[N-].[OH:12][C@H:13]1[CH2:33][C@@:32]2([CH3:34])[C@@H:24]([CH2:25][C@@H:26]([OH:36])[C@:27]2([OH:35])[C:28](=[O:31])[CH2:29][OH:30])[C@H:23]2[C@H:14]1[C@:15]1([CH3:38])[C:20]([CH2:21][CH2:22]2)=[CH:19][C:18](=[O:37])[CH:17]=[CH:16]1>>[OH:12][C@H:13]1[CH2:33][C@@:32]2([CH3:34])[C@@H:24]([CH2:25][C@@H:26]([O:36][CH2:5][C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH2:3])[C@:27]2([OH:35])[C:28](=[O:31])[CH2:29][OH:30])[C@H:23]2[C@H:14]1[C@:15]1([CH3:38])[C:20]([CH2:21][CH2:22]2)=[CH:19][C:18](=[O:37])[CH:17]=[CH:16]1
Reactant: C=C(C=[N+]=[N-])c1ccccc1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Product: C=C(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO)c1ccccc1

Procedure:
A solution of 1-diazo-2-phenyl-2-propene (prepared from 0.3 mole of N-nitrosourethane precursor) in methanolether at 0° is treated with 11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate (84 mmoles) until nitrogen evolution ceases. Solvent removal gives the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.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>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:24])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: Cc1ccccc1B(O)O
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: CC#N
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1C=O

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carbaldehyde (2.1 g, 10 mmol), o-tolylboronic acid (1.5 g, 1.1 eq), tetrakis(triphenylphosphine)palladium (575 mg, 0.05 eq), and sodium carbonate (5.5 g, 5 eq) in MeCN (75 mL) and water (25 mL). After purification, 8-methyl-2-o-tolylquinoline-3-carbaldehyde was obtained as white solid. 1H-NMR (CDCl3) 9.96 (s, 1H), 8.83 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.74 (d, J=6.3 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.36-7.46 (m, 4H), 2.84 (s, 3H), δ 2.30 (s, 3H). Mass Spectrum (ESI) m/e=262 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>O>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Nc3cccc(C(F)(F)F)c3)ccnc12
Temperature: 150 °C
Yield: 156.3 %

Procedure:
A mixture of 4-chloro-8-nitroquinoline (step-2, Intermediate-11, 100 mg, 0.48 mmol) and 3-(trifluoromethyl)aniline (309 mg, 1.92 mmol) was heated at 150° C. for 20 minutes in microwave. Then water was added to the reaction mixture and it was extracted with CHCl3. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 250 mg of the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4.[H-].[Na+].CC1C=CC(S(O[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (110 mg, 0.484 mmol) in DMF (1 mL) was added a suspension of NaH (60.0 mg, 1.45 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (423 mg, 1.45 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 10-methyl-7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine. 1H NMR (CD3OD, Tri-HCl salt) δ (ppm): 8.7 (s, 1H), 8.4 (d, 1H), 8.25 (s, 2H), 7.8 (d, 1H), 5.1 (m, 1H), 4.8-4.6 (m, 2H), 3.9-3.7 (m, 3H), 3.4 (m, 2H), 3.4-3.2 (m, 2H), 2.9-2.7 (m, 2H), 2.8 (s, 3H), 2.5 (s, 3H), 2.3-2.15 (m, 3H). Separation by chiral HPLC provided enantiomers 74a and 74b.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]([C:37]1[N:38]=[C:39]([CH3:50])[N:40](COCC[Si](C)(C)C)[CH:41]=1)#[CH:36]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:8][C:4]1[CH:3]=[C:2]([C:36]#[C:35][C:37]2[N:38]=[C:39]([CH3:50])[NH:40][CH:41]=2)[CH:7]=[CH:6][N:5]=1
Reactant: C#Cc1cn(COCC[Si](C)(C)C)c(C)n1
Reactant: Cc1cc(Br)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Bromo-2-methyl-pyridine (1.92 g, 11.2 mmol) was dissolved in 50 mL dry THF and triethylamine (3.9 mL, 30 mmol) was added. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphin (73 mg, 0.28 mmol) and bis(triphenylphosphin)palladium(II)chloride (327 mg, 0.47 mmol) were added and the reaction mixture was stirred at RT for 20 min. Copper(I)iodide (53 mg, 0.28 mmol) and a mixture of 4-ethynyl-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole and 5-ethynyl-2-methyl-1-(2-trimethyl-silanyl-ethoxymethyl)-1H-imidazole (2.2 g, 9.3 mmol) were added. The reaction mixture was then stirred at RT overnight. The solvent was evaporated. The residue was taken up in 50 mL water and extracted three times with ethyl acetate (70 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 80:20 →0:100 gradient ) and the desired compound was obtained as a mixture of 2 isomers (2.86 g, 94%), MS: m/e=327.2 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[C:6]([CH:11]1[CH2:13][CH2:12]1)=[CH:7][N:8](C)C)[CH3:2].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25]N.Cl>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[N:25]([C:19]2[C:18]([Cl:17])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:24])[N:8]=[CH:7][C:6]=1[CH:11]1[CH2:13][CH2:12]1)=[O:15])[CH3:2]
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C1CC1
Reactant: NNc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C2CC2)cnn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
To a solution of 3-cyclopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester (6.5 mmol, 1.4 g) in ethanol (25 mL) is added 2,6-dichlorophenyl hydrazine hydrochloride (7.2 mmol, 1.5 g) followed by concentrated HCl (100 μL). The reaction is stirred for 4 h at room temperature followed by heating at 85° C. for 18 h. The reaction mixture is adsorbed onto silica gel and purified using a gradient of 0-20% EtOAc/Hexanes to yield the title compound (0.8 g, 34%). LC-ES/MS m/e 325.0 (M+1).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>CN(C)C=O.O>[CH2:1]([CH:3]([C:6]1[C:14]2[N:13]([CH2:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(C)OC(=O)CBr
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)c1cccc2c1n(CC(=O)OC(C)C)c(=O)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (23.2 g, 76.2 mmol) in N,N-dimethylformamide (120 mL) was added potassium carbonate (11.6 g, 83.9 mmol) and isopropyl bromoacetate (10.9 mL, 83.9 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude tert-butyl 4-(1-ethylpropyl)-3-(2-isopropoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate.
Reaction SMILES: O1CCCCC1[N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:9]([C:19]([NH:21][C:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[N:24](C3CCCCO3)[N:23]=2)=O)=[N:8]1.CO.Cl>C1COCC1>[C:30]1([CH3:33])[CH:31]=[CH:32][C:27]([C:25]2[NH:24][N:23]=[C:22]([NH:21][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[NH:7][N:8]=3)[CH:26]=2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2cc(NC(=O)c3cc(-c4ccc(C)cc4)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2cc(CNc3cc(-c4ccc(C)cc4)[nH]n3)n[nH]2)cc1
Temperature: 0 °C

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-yl)-5-p-tolyl-1H-pyrazole-3-carboxamide (142 mg, 0.27 mmol) was suspended in anhydrous THF (10 mL) and borane dimethylsulfide complex (177 μL, 1.86 mmol) was added dropwise. The reaction mixture was stirred under reflux for 16 hrs. The reaction mixture was then cooled down to 0° C. and MeOH (500 μL) was added. The mixture was then stirred for 10 min. Concentrated hydrochloric acid (12 N) was added, until a pH<2 was obtained, and the resulting mixture was stirred under reflux for 16 hrs. The mixture was cooled to room temperature and the precipitate was filtered and added into an aqueous solution of sodium hydroxide (1M). The aqueous phase was extracted with DCM (3×10 mL) after drying the organic layers with Na2SO4, the solvent was evaporated. The residue was purified by chromatography on silica gel column (eluent: EtOAc); 5-p-tolyl-N-((5-p-tolyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-3-amine was obtained as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[N+:20]([O-])=O)=[C:8]([CH:11]=2)[C:9]#[N:10])[CH2:3][CH2:2]1.[Sn](Cl)[Cl:24]>C(O)C.Cl>[ClH:24].[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[NH:12][C:13]4[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=4[N:20]=[C:9]([NH2:10])[C:8]=3[CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cl[Sn]Cl
Reactant: N#Cc1cc(C2CC2)ccc1Nc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NC1=Nc2ccc(F)cc2Nc2ccc(C3CC3)cc21
Yield: 60.7 %

Procedure:
Heat a solution of 5-cyclopropyl-2-(5-fluoro-2-nitro-phenylamino)-benzonitrile (0.447 g, 1.50 mmol) in ethanol (7 ml) to 60° C. Add a solution of tin (II) chloride (0.855 g, 4.51 mmol) in 5.0 N hydrochloric acid (7 ml) and heat the resulting mixture to reflux for 16 hours. Cool the reaction to room temperature, add 25 ml of 5.0 N hydrochloric acid and place the mixture in a freezer for 16 hours. Collect by filtration the precipitated product from the solution. Wash solid with 5.0 N hydrochloric acid to obtain 0.277 g of the title compound (0.91 mmol, 61% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 268(M+1).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([O:18]CC)(=O)[CH2:11][C:12]([O:14]CC)=O>>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH2:11][C:10]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1])=[O:18]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)OCC
Product: O=C(CC(=O)Nc1cccc(Cl)c1Cl)Nc1cccc(Cl)c1Cl
Temperature: 170 °C
Reaction time: 8 h

Procedure:
100 mmol 2,3-dichloroaniline and 50 mmol diethyl malonate were put together and stirred at overnight 170° C. The formed ethanol was distilled off directly (100 mmol≡6.6 mL) on a stream of nitrogen. N1,N3-di(2,3-dichloro-phenyl)-malonamide was formed as one solid block. The reaction was cooled and EtOAc was added. The product had to be crushed with a mortar, because it resembled very hard brick. The crushed material was stirred in EtOAc and filtered. EtOAc added was added twice and the mixture was stirred and filtered each time. 14.7 g N1,N3-di(2,3-dichloro-phenyl)-malonamide was obtained (yield 75.0%, purity 98.4%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18](=[O:21])[CH2:17]2.[Cl-].[Cl-].[Cl-].[Al+3]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[C:12]([CH3:11])[CH:13]=2)[NH:19][C:18](=[O:21])[CH2:17]3)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1cccc2c1NC(=O)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1NC(=O)C2
Temperature: 0 °C

Procedure:
1.92 g (10.9 mmol) 6-chloropyrimidine-4-carboxylic acid chloride, 1.60 g (10.9 mmol) 7-methyl-1,3-dihydro-indol-2-one and 7.33 g (55.0 mmol) aluminium trichloride were heated to 130° C. for 3 h with stirring. The mixture was combined first with ice water and then with EtOAc. The precipitate formed as black flakes was suction filtered and the phases were separated. The aqueous phase was extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(F)c1
Solvent: ClCCl
Product: Fc1cncc(CCl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of (5-fluoropyridin-3-yl)methanol (0.19 g, 1.50 mmol) in DCM (5 mL) was added thionyl chloride (0.19 ml, 2.6 mmol) at 0° C. The reaction was stirred at room temperature for 2 h. The reaction was concentrated and the residue was dried in vacuo to yield 3-(chloromethyl)-5-fluoropyridine (166 mg) which was used without characterization.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([NH:4][C:5]3=[O:12])[CH2:2]1)[CH2:9]2.O(C)S([C:17](F)(F)F)(=O)=O>C(Cl)Cl>[CH3:17][O:12][C:5]1[CH:6]2[CH2:11][CH:1]3[CH2:9][CH:8]([CH2:10][CH:3]([CH2:2]3)[N:4]=1)[CH2:7]2
Reactant: O=C1NC2CC3CC(C2)CC1C3
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC1=NC2CC3CC(C2)CC1C3

Procedure:
To a solution of 4-azatricyclo[4.3.1.13,8]undecan-5-one 3-A (1.00 g, 6.05 mmol) in 10 mL methylene chloride was added methyl triflate (2.98 g, 3 eq) and the reaction was heated at reflux for 20 min, after which time all volatiles were removed under reduced pressure to afford crude 5-methoxy-4-azatricyclo[4.3.1.13,8]undec-4-ene 3-B which was used in the next step without further purification.