Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH3:30])[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N+:12]([O-])=[C:11]3[CH2:19][CH2:20][CH2:21][C:10]=23)[CH2:4][C@H:3]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[CH3:31][C:32]([O:34]C(C)=O)=[O:33]>>[C:32]([O:34][CH:19]1[C:11]2=[N:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]([N:5]3[CH2:6][C@H:7]([CH3:8])[C:2]([OH:1])([CH3:30])[C@H:3]([NH:22][C:23]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:29])[CH2:4]3)=[C:10]2[CH2:21][CH2:20]1)(=[O:33])[CH3:31]
Reactant: C[C@H]1CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A mixture of tert-butyl [(3R,5S)-4-hydroxy-4,5-dimethyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (390 mg, 0.92 mmol) and Ac2O (2 mL) was stirred at 90° C. for 1 h. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The mixture was neutralized with aq. NaHCO3 and then extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 20-80% EtOAc in hexanes to give the desired product as a yellow oil (196 mg, 55% in 2 steps). LCMS calc. for C22H33N4O7 (M+H)+ m/z=465.2. found 465.1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[N:8]=2)[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:51]1([O:57][C:58](Cl)=[O:59])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN1C(=O)CCC1>[C:51]1([O:57][C:58](=[O:59])[NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[N:15]=[C:14]4[C:10]([N:11]=[CH:12][N:13]4[C@@H:16]4[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]4[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[N:8]=3)[CH2:3]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)Oc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture comprising N-((1S,2R,3S,4R)-4-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 22 step 4) (50 mg, 83 μmol) and potassium carbonate (46 mg, 332 μmol) in NMP (1 ml) is treated with phenylchloroformate and stirred at room temperature for 90 minutes. This mixture was used in the next step without purification.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[C:4]([CH3:3])[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]=1[NH2:8]
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of bromine (23.24 mL, 453.5 mmol) in glacial acetic acid (50 mL) was added dropwise over 2 h to a mechanically-stirred suspension of 4-methyl-2-nitroaniline (60.00 g, 394.3 mmol) in glacial acetic acid (200 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature 1 h, and then most of the acetic acid was removed under reduced pressure. The resultant orange solid was dissolved in a mixture of saturated aqueous sodium bicarbonate (1500 mL) and ethyl acetate (500 mL). The layers were separated and the aqueous solution was again extracted with ethyl acetate. The combined organic layers were washed once with water, dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step A as an orange solid melting at 64°-65.5° C. (89.694 g, 98%). 1H NMR (CDCl3): δ2.28 (s,3H), 6.45 (br s,2H), 7.55 (s, 1H), 7.94 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([I:18])=[C:5]([NH:10]C(=O)OC(C)(C)C)[C:6]([F:9])=[CH:7][CH:8]=1>O1CCOCC1.C1COCC1>[F:2][C:3]1[C:4]([I:18])=[C:5]([C:6]([F:9])=[CH:7][CH:8]=1)[NH2:10]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(F)c1I
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Nc1c(F)ccc(F)c1I
Reaction time: 8 h
Yield: 48 %

Procedure:
4M HCl (7.60 mL, 30.4 mmol) in dioxane was added to a solution of tert-butyl (3,6-difluoro-2-iodophenyl)carbamate (1.08 g, 3.04 mmol) in THF (7.60 ml) at room temperature and then stirred overnight. The solvent was removed in vacuo, and then the contents were partitioned between DCM (3×50 mL) and sat'd aqueous sodium bicarbonate. The organics were dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel, eluting 0-50% EtOAc in hexanes over 16 minutes to afford 3,6-difluoro-2-iodoaniline (373 mg, 1.46 mmol) as a tan oil. MS (ESI): m/z=256.2 (M+H-Boc).
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.O[C@@H:23]([CH3:35])[C:24]([N:26]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:28][O:29][CH3:30])=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[C:7]([O:9][C@H:23]([C:24](=[O:25])[N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:31][CH2:32][O:33][CH3:34])[CH3:35])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: COCCN(CCOC)C(=O)[C@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCN(CCOC)C(=O)[C@H](C)OC(=O)/C=C/C(=O)OC
Yield: 16.4 %

Procedure:
Following general procedure B2, (2E)-3-(methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF) (0.50 g, 3.84 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (0.88 g, 4.60 mmol) in 20 mL of dichloromethane (DCM) at ca. 0° C. (2S)-2-Hydroxy-N,N-bis(2-methoxyethyl)propanamide (0.63 g, 3.07 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by silica gel flash column chromatography (Biotage) using ethyl acetate (EtOAc) and hexanes (2:1) afforded 0.16 g (14% yield) of the title compound (32) as a clear oil. 1H NMR (CDCl3, 400 MHz): δ 6.93-6.77 (m, 2H), 5.53 (q, J=6.4 Hz, 1H), 3.80 (s, 3H), 3.58-3.50 (m, 8H), 3.47-3.32 (2s, 6H), 1.49 (d, J=6.8 Hz, 3H). MS (ESI): m/z 318.05 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)[C@@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:7][C@@H:8]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(CNC[C@H](O)[C@@H](Cc2ccc(F)c(F)c2)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2ccc(F)c(F)c2)c1
Reaction time: 12 h
Yield: 109 %

Procedure:
A solution of (1R,2S)-[1-(3,4-Difluorobenzyl)-2-hydroxy-3-(3-methoxy-benzylamino)-propyl]-carbamic acid tert-butyl ester (0.04 g, 0.09 mmol) in methylene chloride (1 mL) was treated with 4 N HCl in dioxane (1 mL) at ambient temperature in one portion. The reaction was stirred for 12 hours and the solvent removed at reduced pressure to give the product as a solid (0.033 g, 98%). MS: 337 (M+H, 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:12]#[N:13])[CH2:8][CH2:9][CH3:10]>CCOCC>[C:20]1([C:11]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][NH2:13])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCC(C#N)(Cn1cncn1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCC(CN)(Cn1cncn1)c1ccccc1
Yield: 68.1 %

Procedure:
To a 5 liter flask stirring under nitrogen, fitted with a mechanical stirrer, was charged 21 g (0.55 mole) of lithium aluminum hydride. To the lithium aluminum hydride was charged 127 g (0.50 mole) alpha-butyl-alpha-phenyl-1H-1,2,4-triazole-1propanenitrile in 2500 mL of dry ether over 2.5 hours. The reaction was stirred for an additional 5 hours after which GLC indicated the reaction was complete. The reaction was quenched with sodium sulfate, filtered and the organic phase separated. The aqueous phase was extracted with 1000 mL of ether. The organics were combined, washed with 3×1.5 liters of ice water, dried, filtered and concentrated without external heating and gave 88 g (69.2% yield) of a pale green oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>CN(C=O)C.[Cu](I)I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)-c1nc(-c3ccccn3)cn1CCO2
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.512 mmol), 2-tributylstannanylpyridine (226 g, 0.614 mmol), Pd2(PPh3)2Cl2 (36 mg, 0.05 mmol) and copper iodide (29 mg, 0.15 mmol) in DMF (4 mL) was purged with nitrogen and then heated at 100° C. for 1 h using microwave irradiation. The reaction mixture was diluted with MeOH (20 mL) and then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% MeOH in DCM followed by Si-PCC, gradient 0-7% MeOH in EtOAc) affording the title compound as a cream solid (140 mg, 80%). LCMS: RT 2.52 min [M+H]+ 341.8/343.8.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([S:13](Cl)(=[O:15])=[O:14])=[C:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]=2[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][S:13]([C:7]2[S:6][C:5]3[CH:17]=[CH:18][C:2]([F:1])=[CH:3][C:4]=3[C:8]=2[CH2:9][CH:10]([CH3:12])[CH3:11])(=[O:15])=[O:14])=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:22]=1
Reactant: CC(C)Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12

Procedure:
This compound was prepared in analogy to Example 1 starting from 5-fluoro-3-isobutyl-benzo[b]thiophene-2-sulfonyl chloride (044 g), 2-amino-5-bromobenzotrifluoride (3.44 g) in pyridine (5 ml) for 18 h at rt to obtain the desired compound (0.24 g) as a colorless solid. MS (ISN): 508.2, 510.3 (M−H)−
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.ClC(OCC)=O.Cl.[CH3:26][NH:27][OH:28]>ClCCl.C(N(CC)CC)C>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([N:27]([OH:28])[CH3:26])=[O:18])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CNO
Reactant: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)N(C)O)cc1
Reaction time: 16 h

Procedure:
A solution of 12.05 g of (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-2-propenoic acid in 350 ml of dichloromethane and 9.7 ml triethylamine, is cooled in an ice bath. To this stirred solution is added 7.0 ml of ethyl chloroformate dropwise. After four hours at ice-bath temperature, 20.7 ml of triethylamine is added, followed by 12.6 g of N-methylhydroxylamine hydrochloride and the mixture is kept at room temperature for 16 hours. This mixture is washed with cold 0.3 N aqueous hydrochloric acid, ice cold sodium bicarbonate and brine. The organic phase is dried over MgSO4, treated with charcoal and filtered. The solvent is evaporated at 50° under reduced pressure and the product is crystallized from ether to give (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-N-hydroxy-N-methyl-2-propenamide, m.p. 143°-145°, the compound of formula IV wherein R1 and R2 represent methyl at the 2 and 5 positions, R4 represents methyl, and R3, R8 and R9 represent hydrogen; the compound may also be named (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-N-methyl-2-propenohydroxamic acid. The product can also be recrystallized from ethyl acetate (with charcoal and silica gel).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:23])([F:25])[F:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-(3,4-Dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.38) (0.405 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as light brown foam (0.41 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2[NH:16][C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[NH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]2=[N:16][C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:18][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCCOC(=O)Cl
Reactant: CC(C)NC(=N)NC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Product: CCCCCCOC(=O)N=C(N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1)NC(C)C

Procedure:
Compound 4e was prepared by the same method for preparation of 4b, using pure compound 4 (0.800 g, 2.34 mmol) and hexyl chloroformate as starting materials to yield compound 4e as a white color crystal (0.354 g, 32%). 1H NMR (300 MHz, CDCl3) δ 12.45 (s, 1H), 7.57–7.54 (m, 2H), 7.31–7.27 (dd, J=8.5 and 2.4 Hz, 1H), 4.25 (t, J=6.8 Hz, 2H), 4.12 (m, 1H),1.74 (m, 2H), 1.35 (m, 6H), 1.25 (d, J=6.6 Hz, 6H), 0.93 (t, J=6.4 Hz, 3H); 13C NMR: δ170.78, 168.50, 159.20, 155.93, 154.15, 132.56, 132.18, 131.50, 130.41, 128.62, 125.61, 31.31, 28.38, 25.32, 22.49, 22.30, 14.00. MS m/z 470 (M+), 418, 416, 368, 342, 314, 272, 230, 174.
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3][NH:2]1.[CH:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[CH2:11].C(O)(=O)C>CO>[N:15]1[CH:16]=[CH:17][C:12]([CH2:10][CH2:11][N:2]2[CH2:3][C@H:4]3[C@H:9]([CH2:8][CH:7]=[CH:6][CH2:5]3)[CH2:1]2)=[CH:13][CH:14]=1
Reactant: C=Cc1ccncc1
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Solvent: CC(=O)O
Solvent: CO
Product: C1=CC[C@H]2CN(CCc3ccncc3)C[C@H]2C1

Procedure:
A mixture of 0.64 g of cis-3a,4,7,7a-tetrahydroisoindoline, 0.6 mL of 4-vinylpyridine, 0.4 mL of acetic acid and 10 mL of methanol was heated under reflux for 16 hours. Removal of the solvent and short-path distillation of the residue (160° bath temperature, 0.002 mm) gave 0.74 g. of cis-2-(4-pyridylethyl)-3a,4,7,7a-tetrahydropyridine. 1H NMR (in CDCl3) δ8.5 (d, 2H); 7.1 (d, 2H); 5.8 (m, 2H); 3.0 (m, 2H); 2.7-2.8(m, 4H); 2.4 (m, 2H); 2.2-2.3 (m, 4H) and 1.9 (d, 2H). The dihydrochloride hemi-hydrate had an indefinite melting point after crystallization from 2-propanol.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:8]([O:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(Cl)cc2Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (20 g, 96.61 mmol) in DMSO (200 ml) was added 2,4-dichlorophenol (15.8 g, 96.93 mmol) and potassium carbonate (26.7 g, 193.18 mmol). The resulting solution was stirred overnight at 90° C. and then quenched by the addition of water (1000 ml). The resulting solution was extracted with ethyl acetate (3×500 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(2,4-dichlorophenoxy)-2-nitroaniline as a yellow solid (23 g, 71%). Next, the 4-chloro-5-(2,4-dichlorophenoxy)-2-nitroaniline (22 g, 65.96 mmol) was added to ethanol (200 ml) and hydrogen chloride (16 ml, 197.9 mmol). This was followed by the addition of Zn powder (21.4 g, 395.8 mmol) at room temperature in portions. The resulting solution was stirred for 4 h at 85° C. and then concentrated under vacuum. The residue was dissolved in water (500 ml), adjusted pH to 8 with aqueous sodium bicarbonate and extracted with ethyl acetate (4×200 ml). The combined organic layers were dried and concentrated under reduce pressure to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to afford 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine as a red oil (15 g, 75%). Finally, a solution of 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine (14 g, 46.12 mmol) in heptafluorobutanoic acid (150 ml) was stirred overnight at 80° C. in an oil bath. The reaction was then quenched by the addition of water (400 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 2%˜10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-dichlorophenoxy)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (10.4705 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]=[C:17]=[S:18])=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:20][C:21]1[C:22]([NH2:45])=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([CH:39]=1)[C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]1)=[O:27]>CN(C=O)C.O>[Cl:1][C:2]1[C:15]([NH:16][C:17]([NH:20][C:21]2[CH:39]=[C:25]([C:26](=[O:27])[NH:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([C:35]([F:38])([F:36])[F:37])[CH2:33][CH2:34]3)[C:24]([O:40][CH2:41][CH:42]([F:43])[F:44])=[N:23][C:22]=2[NH2:45])=[S:18])=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCC(F)F)nc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(NC(=S)Nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)nc2N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2,4-Dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (100 mg, 0.30 mmol) is added to 5,6-diamino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (120 mg, 0.30 mmol) in DMF (5 mL) and it is stirred at rt overnight. The reaction mixture is diluted with water, extracted with EtOAc, the organic layer is washed with water, dried and concentrated to give the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.C([NH:31][CH2:32][CH:33]([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])C1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:35]([O:34][CH:33]([O:37][CH2:38][CH3:39])[CH2:32][NH:31][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)=[O:23])[CH3:36]
Reactant: CCOC(CNCc1ccccc1)OCC
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1)OCC
Reaction time: 23 h
Yield: 46 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (prepared according to the methods described by Barth, et al. in U.S. Pat. No. 5,624,941); 740 mg, 2.01 mmol) and N-benzyl-N-(2,2-diethoxyethyl)amine (450 mg, 2.01 mmol) in methylene chloride (6.5 ml) at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (464 mg, 2.42 mmol) and then diisopropylethylamine (0.42 ml, 2.2 mmol), dropwise. After stirring for 23 hours, the reaction mixture was concentrated, in vacuo, and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and concentrated, in vacuo. The crude material (1.05 g) was purified on a Biotage™ Flash 40S column using 0-20% ethyl acetate in hexanes as eluant to afford I-1A-1a as a foam (534 mg, 46%): +ESI MS (M+1) 572.1; 1H NMR (500 MHz, CD2Cl2) 1:1 mixture of rotamers, δ 7.51 (br s, 0.5H), 7.47 (d, J=2.1 Hz, 0.5H), 7.38-7.34 (m, 2H), 7.38-7.23 (m, 9H), 7.18-7.11 (m, 2H), 7.03 (s, 0.5H), 6.95 (s, 0.5H), 5.22 (s, 1H), 4.91 (s, 1H), 4.83-4.79 (m, 1H), 3.56-3.07 (m, 6H), 1.20 (t, J=7.0 Hz, 3H), 1.07 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([C:33]([F:35])([F:34])[F:36])[CH:22]=2)=[O:19])=[CH:37][C:38]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(NC2CC2)nn1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CC5)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The intermediate compound 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide was made as for Example 18 (Step 1 to 3) with the spectra below: 1H NMR (300 MHz, DMSO-d6) δ: 10.78 (1H, s), 8.55 (1H, d, J=2.1 Hz), 8.26 (1H, s), 8.22 (1H, s), 8.11 (1H, s), 7.99-8.03 (1H, dd, J=2.1 and 8.1 Hz), 7.76-7.80 (2H, m), 7.49 (1H, s), 2.19 (3H, s). LCMS: m/z [M+H]+ 505.9663.