Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:35][CH2:36][CH3:37])=[C:9]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:35][CH2:36][CH3:37])=[C:9]([C:11]2[N:12]([C:32]([N:50]3[CH2:51][CH2:52][N:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:48][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 20% of 1:1 ethanol/acetonitrile in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C38H49N4O4SCl2 [(M+H)+] 727.2846, observed 727.2847.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][C:5]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:7]=1C(O)=O.C(=O)=O>C(O)CC>[ClH:1].[NH2:2][C:3]1[S:4][C:5]([CH:11]([CH3:13])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(C(=O)O)c(N)s1
Agent: Cl
Agent: O=C=O
Solvent: CCCO
Product: CC(C)c1ccc(N)s1
Temperature: 80 °C
Yield: 52 %

Procedure:
Concentrated hydrochloric acid (125 ml) was heated to 60° C. with stirring, and a solution of 2-amino-5-isopropylthiophene-3-carboxylic acid (18.52 g, 0.1 mol) in 200 ml of n-propanol was added dropwise while the temperature was raised gradually to 80° C. A slow evolution of carbon dioxide, subsiding after 2 hours was observed. The mixture was evaporated in vacuo, and stripped five times with 200 ml of propanol to remove water. The residue was dissolved in 25 ml of propanol, and reprecipitated by the addition of 300 ml of tetrahydrofuran. After stirring overnight the precipitate was filtered off to yield 9.23 g (52%) of 2-amino-5-isopropylthiophene hydrochloride melting with destruction at 152°-153° C. 1H-NMR (DMSO-d6, δ): 1.2 (d, 6H), 3.2 (m, 1H), 6.7 (d, 1H), 6.8 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.O.[NH2:22][NH2:23]>N1C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[C:2]([NH:22][NH2:23])[N:3]=[N:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2cnnc(Cl)c2-c2ccncc2)cc1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
3-Chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazine (5.1 g, 16.9 mmol) was dissolved in pyridine (20 mL) and hydrazine mono-hydrate (17.0 mL, 350.5 mmol) was added. The reaction mixture was stirred at reflux for 40 min. After this time, the reaction mixture was cooled to RT and then concentrated to half of the original volume under reduced pressure. The resultant mixture was diluted with water (100 mL). The yellow colored solid was collected by filtration and rinsed thoroughly with water. The solid was dried in a vacuum oven at 40° C. to give the title compound, 1-(5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3-yl)hydrazine, (4.4 g, 88%) as a yellow powder. HPLC: 1.01 min; MS, M+H=298.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:41])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=4[Cl:40])[O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])=[O:23])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+:44]>C1COCC1.O>[Na+:44].[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[C:26]1[O:27][C:28]([C:29]([F:32])([F:30])[F:31])=[C:24]([C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:4][C:3]([O-:42])=[O:2])[CH2:10][CH2:9]3)=[CH:12][CH:13]=2)=[O:41])=[O:23])[N:25]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4c(Cl)cccc4Cl)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4c(Cl)cccc4Cl)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-{[2-(2,6-dichlorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetate methyl ester (150 mg, 0.239 mmol) was put into THF/water (20 mL, 3:1) solvent, then NaOH (14.37 mg, 1.437 mmol) was added thereto and stirred at room temperature for 24 hours. After THF was removed, a desired sodium salt solid was washed with water to obtain a final compound (150 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29]([O:31]CC)=O)[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>>[F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29]([NH:37][CH2:38][C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[O:31])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: NCc1ccncc1
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCc3ccncc3)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(aminomethyl)pyridine employing methods similar to those described in Example 5 and was obtained as a white solid; 1H NMR (CDCl3) δ 10.59 (1H, t, J˜6 Hz), 8.64 (2H, d, J=6 Hz), 8.62 (1H, d, J=1.2 Hz), 7.86 (2H, d, J=8 Hz), 7.55 (2H, d, J=6 Hz), 7.22 (2H, d, J=8 Hz), 7.06 (1H, s), 7.00 (4H, m), 5.43 (2H, br), 4.78 (2H, d, J=6 Hz), 4.05 (2H, s), 3.04 (3H, s); ES+ MS: 573 (M+H+, 100).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[N:20]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[N:19]1([CH2:18][CH2:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(CCCCn3ccnn3)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(CCCCn2ccnn2)cc1
Yield: 99.8 %

Procedure:
1-[4-(4-benzyloxyphenyl)butyl]-1H-1,2,3-triazole (0.38 g) was dissolved in methanol (7.6 ml); 10% palladium carbon (0.1 g) was added, followed by vigorous stirring in a hydrogen atmosphere for 14 hours. The catalyst was filtered off; the filtrate was concentrated to dryness under reduced pressure to yield the titled compound (0.268 g) as a crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[N:10]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+].C(OCC)C>C(Cl)Cl.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[N:10]1
Reactant: OCc1cnnn1-c1c(Cl)cccc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: O=Cc1cnnn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (1.87 g, 1 equiv) in methylene chloride (110 mL) is added Dess-Martin oxidant (4.20 g, 1.3 equiv). The reaction mixture is allowed to stir at room temperature for 3 h. The reaction is incomplete as evidenced by TLC. The reaction mixture is treated with Dess-Martin oxidant (1.20 g). The reaction mixture is allowed to stir at room temperature for an additional 2 h. The reaction mixture is treated with 80 mL 1.5 N sodium hydroxide and 40 mL diethyl ether. The resulting solution is allowed to stir at room temperature for ten minutes. The reaction mixture is diluted with 120 mL water and extracted three times with chloroform. The combined organic layers are dried over magnesium sulfate and filtered though a plug of silica gel eluting with chloroform/ethyl acetate (3:1, 200 mL). The filtrate is concentrated under reduced pressure to give the title compound (1.76 g, 94%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20]O)[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.B(Br)(Br)[Br:23]>ClCCl.C(=O)=O.CC(C)=O>[Br:23][CH2:20][C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CO)c3o2)cc1
Reactant: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Benzyl Alcohol 3 (0.500 g, 1.759 mmole) was dissolved in dichloromethane (50 mL) and cooled to −78° C. in dry ice/acetone bath. To this solution, boron tribromide (1.0 M in dichloromethane), (7.04 mL, 7.05 mmole) was added drop wise over 15 minutes. After 30 minutes, the dark orange solution was allowed to come to room temperature and reacted for an additional 4 hours. The solution was concentrated and added to saturated sodium bicarbonate and extracted with ethyl acetate. Organic layers were combined and washed with water, brine, and dried over magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 7:3) to afford 0.495 g (88%) of benzyl bromide 4 as a white solid: Mp=337–339° C.; 1H NMR (DMSO-d6) δ 7.90 (s, 2 H),), 7.74 (d, 2 H, J=8.8 Hz), 7.06 (s, 1 H), 6.89 (d, 2 H, J=8.7 Hz), 6.86 (d, 1 H, J=2.5 Hz), 6.77 (d, 1 H, J=2.2 Hz); MS 317/319 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17])#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:17])#[N:12]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: c1ccc2c(c1)CCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)N2CCCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
1,2,3,4-tetrahydroquinoline (4.2 g, 31 mmol) was added dropwise to a solution of 3-cyanobenzoyl chloride (5.2 g, 31 mmol) and triethylamine (3.1 g, 31 mmol) in dichloromethane (125 ml) while cooling in an ice/water bath. The mixture was allowed to warm to RT and stirred for 18 h. It was washed with 0.3M potassium hydrogen sulphate solution, saturated sodium hydrogen carbonate solution and brine. The organic phase was filtered through phase separation paper and reduced to yield 1-(3-cyanobenzoyl)-1,2,3,4-tetrahydroquinoline (7.1 g, 86%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]([C@H:15]([OH:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C@@H:9]([C@H:15]([OH:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)[C@H]([C@H](O)C(C)(C)C)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H](N)[C@H](O)C(C)(C)C
Yield: 69.8 %

Procedure:
In a pear flask, at rt, ethyl (2S*,3R*)-2-(dibenzylamino)-3-hydroxy-4,4-dimethyl-pentanoate (2.0 g, 5.6 mmol) was dissolved in EtOH (110 mL) and passed through the H-Cube® hydrogenator flow reactor, using 10% Pd/C as catalyst [flow:1.0 mL/min; P=1.0 bar, T=70° C.]. After evaporation of the solvent, the title compound (0.74 g, 70%) was obtained as yellowish oil and used without further purification in the following step. MS (ESI) m/z: 190 [M−H]+. 1H NMR (DMSO-d6) δ 0.90 (s, 9H), 1.20 (t, J=7.11 Hz, 3H), 3.35 (d, J=2.95 Hz, 1H), 3.44 (d, J=2.92 Hz, 1H), 4.05-4.13 (m, 2H).
Reaction SMILES: [C:1]([Cl:4])(=O)[CH3:2].Cl.[CH2:6]([O:8][C:9](=[O:28])[C@H:10]([OH:27])[CH2:11][C@H:12]([NH2:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH3:7]>C(O)CCC>[CH2:6]([O:8][C:9](=[O:28])[C@H:10]([OH:27])[CH2:11][C@H:12]([NH2:26])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:1][CH3:2].[ClH:4]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
1-Butanol (40 mL, 400 mmol) was cooled in an ice bath and acetyl chloride was added dropwise until a concentration of 4N HCl was achieved. The mixture was warmed to room temperature. (2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 250 mg, 710 μmol) was added to the acidified butanol (15 mL) and the mixture was capped and heated to 80° C. for 3 hours. The resulting product was dried under vacuum to yield the title compound as a white/orange flaky solid HCl salt (220 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(Br)cc([N+](=O)[O-])c1
Yield: 80 %

Procedure:
To a solution of 1-bromo-3,5-dinitrobenzene (20 g, 80.97 mmol) in acetic acid (120 ml) at 90° C. was added iron powder (11.3 g, 202.4 mmol, 2.5 eq) slowly portionwise over a period of 30 min (caution: highly exothermic reaction). After completion of the addition, the mixture was quenched by the addition of crushed ice. The precipitate formed was filtered and was washed with cold water to obtain orange solid. The solid was dried under vacuum to give the product in 80% yield (14 g). 1H NMR (300 MHz, CDCl3): δ 10.55 (br s, 2H), 8.46 (s, 1H), 8.19 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[C:17]([F:20])=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:22][C:23](=[O:38])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)(C)(C)C.[C:40](O)([C:42]([F:45])(F)F)=O>C(Cl)Cl>[F:45][C:42]1[CH:40]=[C:17]([F:20])[CH:16]=[CH:15][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[N:33]4)[CH:27]=3)[CH2:24][C:23](=[O:38])[NH:22][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-c3ccc(F)cc3F)cc2N1

Procedure:
Prepared from {2′,4′-difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K90) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (78 mg).
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.COC1C=CC(C=O)=CC=1>>[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:4][CH3:3])=[CH:22][CH:23]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: O=C(O)C(F)(F)F
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)cc1
Yield: 16 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-methoxybenzaldehyde were reacted to produce the title compound (16%). 1H NMR (d-chloroform): 15.54 (br s, 1H) 8.23 (d, J=9 Hz, 1H), 8.06 (d, J=9 Hz, 2H), 7.79 (s, 1H), 7.06 (d, J=9 Hz, 2H), 6.51 (m, 1H), 6.42 (m, 1H), 5.86 (br s, 1H), 5.46 (br s, 1H), 5.39 (t, J=8 Hz, 1H), 3.91 (s, 3H), 3.17 (s, 1H), 3.05 (s, 1H), 2.68 (d, J=9 Hz, 1H), 2.33 (d, J=9 Hz, 1H), 1.68 (d, J=10 Hz, 1H). MS: 466.07 (M+H). HPLC retention time: 2.42 minutes (G Method).
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[C:10]([OH:21])(=[O:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.[CH2:22]=O>O>[C:15]([C:14]1[CH:18]=[C:19]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:21])[O:20][CH2:22]2)([OH:17])=[O:16]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 143 °C
Yield: 82 %

Procedure:
Oleum (20-25% SO3 43 kg) is charged into a reactor. Terephthalic acid (13 Kg) and then paraformaldehyde (3.8 Kg) is added. The mixture is agitated at 138-148° C. for 4½ hours. Water (87 L) is added and the temperature is adjusted to about 100° C. The precipitate is filtered of, washed with water and suspended in water. The pH of the suspension is adjusted to about 7 with NaOH (about 10%), activated carbon, 0.5 Kg is added, and then the mixture is filtered, the precipitate is rinsed with water. The temperature of the filtrate is adjusted to about 85° C. and the pH is adjusted to about 2 with 96% sulfuric acid. The 5-carboxyphthalide precipitated is separated by filtration washed and dried. Yield 82%.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCCCCCCN3CCOCC3)cccc21
Solvent: CO
Product: NCCCCCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 8-morpholinyloctylphthalimide (275 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([Cl:12])[CH:3]=1.Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:12])[CH:3]=1
Reactant: Nc1nc2cc(Cl)cc(Cl)n2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.00 g; 4.93 mmol; 1.00 eq.) and nicotinoyl chloride hydrochloride (1052.16 mg; 5.91 mmol; 1.20 eq.) as a yellowish solid (1.06 g, 70%). HPLC, Rt 1.61 min. (purity 92.4%). LC/MS, M+(ESI): 307.7, M−(ESI): 305.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3I)[CH:13]=2)=[CH:4][CH:3]=1.[S:18]1[CH:22]=[N:21][N:20]=[C:19]1[NH:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:28][CH:29]=1>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:26]3[CH:25]=[C:24]([NH:23][C:19]4[S:18][CH:22]=[N:21][N:20]=4)[CH:29]=[CH:28][CH:27]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(Nc3nncs3)c2)OC1(C)C
Reactant: Fc1ccc(-c2ccc3c(I)cnn3c2)cc1
Solvent: COCCOC
Product: Fc1ccc(-c2ccc3c(-c4cccc(Nc5nncs5)c4)cnn3c2)cc1
Temperature: 150 °C
Yield: 8.8 %

Procedure:
A mixture of 6-(4-fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyridine (150 mg, 0.44 mmol), 3-([1,3,4]thiadiazol-2-ylamino)-phenyl boronic acid pinacol ester (190 mg, 0.62 mmol) and PdCl2ddpf (32 mg, 0.04 mmol) in DME (1.5 ml) and 2N Na2CO3 (aq, 1.5 ml) in a microwave vial was deoxygenated by bubbling N2 through for 30 seconds. The vial was sealed and then stirred and heated at 150° C. in the microwave for 30 minutes. After cooling to RT the mixture was partitioned between CH2Cl2/H2O. The organic layer was evaporated and the residue was purified by preparative HPLC to give the title compound (15 mg, solid).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitro-3,4-dihydroquinolin-2(1H)-one (5 g, 25.61 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride (7.38 g, 51.23 mmol) were weighed into a round bottom flask and stirred in DMF (50 mL). To this solution/suspension was added potassium carbonate (21.59 g, 156.2 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then poured into ice water (150 mL) and extracted with ethyl acetate (2×100 mL). The combined organics were washed with water (1×) and brine (1×). The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was chromatographed in 0-20% (2M NH3 in MeOH) in 1:1 dichloromethane and ethyl acetate, giving a yellow solid. Yield: 5.8 g, 84%. 1H NMR (CDCl3) δ 8.14 (dd, 1H, J=9.0, 3.0 Hz) 8.06 (d, 1H, J=3.0 Hz), 7.16 (d, 1H, J=9.0 Hz), 4.08 (t, 1H, J=7.5 Hz), 3.00 (t, 1H, J=7.5 Hz), 2.70 (t, 1H, J=7.5 Hz); 2.51 (t, 1H, J=7.5 Hz), 2.31 (s, 6H).
Reaction SMILES: C([C:3]1([C:33]([O-:35])=[O:34])[C:8]2[C:9]3[CH:15]=[C:14]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:13]=[C:12]([Cl:25])[C:10]=3[O:11][C:7]=2[CH2:6][CH2:5][N:4]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])C.O.[OH-].[Li+].Cl>O.O1CCCC1>[C:29]([O:28][C:26]([N:4]1[CH2:5][CH2:6][C:7]2[O:11][C:10]3[C:12]([Cl:25])=[CH:13][C:14]([S:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)(=[O:17])=[O:18])=[CH:15][C:9]=3[C:8]=2[CH:3]1[C:33]([OH:35])=[O:34])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCC1(C(=O)[O-])c2c(oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1C(=O)O
Reaction time: 2 h
Yield: 135.5 %

Procedure:
To a stirred solution of the product of Example 85, step C (80 mg, 0.12 mmol) in water (5 mL) and tetrahydrofuran (5 mL) was added lithium hydroxide monohydrate (84 mg, 2.0 mmol) at ambient temperature. After 2 h, 1 M HCl solution (3 mL) was added. The mixture was extracted with dichloromethane (2×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 2-(tert-butoxycarbonyl)-6-chloro-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine-1-carboxylic acid (80 mg, 99%) as a colorless oil which was used directly in the next step.