Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5](Cl)[CH2:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cu][C:14]#[N:15]>CN1CCCC1=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:14]#[N:15])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: NC1=C([N+](=O)[O-])CN(Cl)C(Cl)=C1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A stirred suspension of 4-amino-1,6-dichloro-3-nitro-pyridine (17.5 g, 84.1 mmol) and copper (i) cyanide (15.1 g, 168.3 mmol) in 170 ml of 1-methyl-2-pyrrolidinone was lowered into an oil bath preheated to 180° C. and stirring continued for 30 minutes. The mixture was allowed to cool and diluted with ethyl acetate (700 ml) and water (700 ml) and the resultant suspension filtered. The organic layer was separated and further washed with water (500 ml) and 0.1N HCl (500 ml). The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid which was washed with diethylether and dichloromethane to afford 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (8 g).
Reaction SMILES: [S-]C#N.[K+].[CH:5]1([O:10][CH2:11][C:12]([NH:14][NH2:15])=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.[N:16]([C:19]([C:21]1[CH:37]=[CH:36][C:24]([O:25][C@@H:26]2[CH2:31][CH2:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]2)=[CH:23][CH:22]=1)=[O:20])=[C:17]=[S:18]>C(#N)C>[CH:5]1([O:10][CH2:11][C:12]2[S:18][C:17]([NH:16][C:19]([C:21]3[CH:37]=[CH:36][C:24]([O:25][C@@H:26]4[CH2:27][CH2:28][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH2:31]4)=[CH:23][CH:22]=3)=[O:20])=[N:15][N:14]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NNC(=O)COC1CCCC1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)N=C=S)cc2)CC1
Agent: N#C[S-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(COC4CCCC4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.4 g of cis-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid is placed in 10 mL of dichloromethane with stirring, at room temperature, under a nitrogen atmosphere. 0.18 mL of oxalyl chloride (2.16 mmol, 1.5 eq.) and 2 drops of dimethylformamide are successively added. The reaction medium is stirred for 2 hours and concentrated under vacuum. The methyl cis-4-(4-chlorocarbonylphenoxy)cyclohexanecarboxylate formed is dissolved in 15 mL of acetonitrile and placed under nitrogen. The mixture is cooled in an ice bath and 0.210 g of potassium thiocyanate (2.16 mmol, 1.5 eq.) is added. The reaction mixture is stirred at room temperature for 1 hour 30 minutes. 0.455 g of cyclopentyloxyacetic acid hydrazide (2.87 mmol, 2 eq.) dissolved in 5 mL of acetonitrile is then added to the methyl cis-4-(4-isothiocyanatocarbonylphenoxy)cyclohexanecarboxylate obtained and the mixture is refluxed for 2 hours 30 minutes and then left to stand at room temperature for 36 hours. The precipitate formed is filtered off and washed with acetonitrile. 0.450 g of methyl cis-4-[4-(5-cyclopentyloxymethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylate is obtained.
Reaction SMILES: Cl[CH:2]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)[CH:3]([N:5]1[C:9](=O)CCC1=O)O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[N:34]C(N)=[N:32][CH:31]=2)=[CH:26][C:25]=1[F:37]>C(O)CCC>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][C:9]3[N:34]([C:2]([CH2:12][C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)=[CH:3][N:5]=3)[N:35]=2)=[CH:26][C:25]=1[F:37]
Reactant: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Solvent: CCCCO
Product: Fc1cc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)ccc1Br
Temperature: 110 °C
Reaction time: 18 h
Yield: 6.7 %

Procedure:
1-(2-Chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11, 228 g, 0.74 mol, 1.1 equiv) and 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (7, 181 g, 0.673 mol) were suspended in 1-butanol (1800 mL) and the resulting suspension was heated to 110° C. and stirred at 110° C. for 18 h (the reaction mixture becomes homogeneous at this point). The reaction mixture was then gradually cooled down to room temperature before being further cooled down to 10° C. in an ice bath. The resulting yellow solid was collected by filtration (save the 1-butanol filtrates), washed with cold 1-butanol (3×100 mL) and dried by suction. This solid was then suspended in the saturated aqueous sodium bicarbonate solution (NaHCO3, 500 mL) and the resulting suspension was stirred at room temperature for 1 h to neutralize the corresponding hydrochloride salt. The free base was then filtered, washed with water (500 mL) and dried in a vacuum oven at 45° C. for 18 h to afford the first crop of the crude 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline (12, 125.1 g, 292.3 g theoretical, 42.8% yield). The 1-butanol filtrates were then concentrated under the reduced pressure and the resulting solids were dissolved in dichloromethane (CH2Cl2, 2 L). The solution was wash with the saturated aqueous sodium bicarbonate solution (NaHCO3, 1 L), dried over sodium sulfates (Na2SO4), and concentrated under the reduced pressure. The residue was then purified by flash column chromatography (SiO2, 0-10% MeOH—CH2Cl2 gradient elution) to afford the second crop of 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)-quinoline (12, 19.7 g, 292.3 g theoretical, 6.7% yield; total 144.8 g, 292.3 g theoretical, 49.5% yield) as yellow solids. For 12: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 9.11 (dd, 1H, J=4.98, 1.55 Hz), 8.85 (d, 1H, J=8.09 Hz), 8.25-8.18 (m, 2H), 8.12-8.00 (m, 3H), 7.93-7.86 (m, 3H), 4.70 (s, 2H); C21H13BrFN5 (MW 434.26), LCMS (EI) m/e 434.00/435.95 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][CH:28]([CH3:45])[CH2:29][CH2:30][NH:31][C:32]1[S:33][CH:34]=[C:35]([C:37]2[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=2)[N:36]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([C:35]2[N:36]=[C:32]([NH:31][CH2:30][CH2:29][CH:28]([CH3:45])[CH3:27])[S:33][CH:34]=2)=[CH:44][CH:43]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)CCNc1nc(-c2ccc(CN)cc2)cs1
Solvent: Cc1ccccc1
Product: CC(C)CCNc1nc(-c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)cs1
Yield: 75 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (380 mg, 0.89 mmol) with 4-[2-(3-methyl-butylamino)-thiazol-4-yl]-benzylamine (443 mg, 1.6 mmol) in toluene (12 mL). Purify the crude mixture by chromatography on silica gel (25 g) eluting with hexane/(EtOAc with 1% methanol) (20:1 to 7:3 gradient) to obtain 7-chloro-6-{4-[2-(3-methyl-butylamino)-thiazol-4-yl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (368 mg, 75%). MS (ES+) m/z: 551.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: Clc1ccc2ccccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2ccc3ccccc3n2)CC1
Yield: 7.5 %

Procedure:
Using the procedure from Example 1A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloroquinoline (124 mg, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (11 mg), a white solid, in 8% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][CH:13]=4)[C:4]=2[CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][CH:13]=4)[C:4]=2[CH:3]=1
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cccc1c32
Reactant: Nc1ccccc1Cl
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-n2c3ccc(Nc4ccccc4Cl)cc3c3cccc1c32

Procedure:
66.2 g (183 mmol) of 3-bromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine (Br-1), 28 g (220 mmol) of 2-chlorophenylamine, 1.5 g of DPPF (2.7 mmol), 0.5 g of palladium(II) acetate and 45 g of sodium tert-butoxide (486 mmol) are heated at the boil in 1.5 l of toluene for 18 h under a protective atmosphere. The mixture is subsequently partitioned between toluene and water, and the organic phase is washed three times with water and dried over Na2SO4 and evaporated in a rotary evaporator. The residue remaining is recrystallised from heptane/ethyl acetate. The yield is 43 g (107 mmol, 59%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[O:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14]>>[Br:8][C:4]1[N:3]=[C:2]([N:11]2[CH2:12][CH2:13][O:9][C:10]2=[O:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=C1NCCO1
Product: O=C1OCCN1c1cccc(Br)n1

Procedure:
Prepared according to the procedure described in Example 139, Step 1, using 2,6-dibromo-pyridine and oxazolidin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1cccc(F)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1cccc(F)c1

Procedure:
In close analogy to the procedure described above, 2-(3-fluoro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: Br.[NH:2]1[CH2:6][CH2:5][C@H:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:3]1.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][N:2]2[CH2:6][CH2:5][C@H:4]([S:7][C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[CH2:3]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCCCc1ccccc1
Reactant: Oc1ccc(S[C@H]2CCNC2)cc1
Agent: Br
Solvent: ClC(Cl)Cl
Product: Oc1ccc(S[C@H]2CCN(CCCCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=328.3 (M+H+) and [α]D20=−6.26° (c=0.61, chloroform) was prepared from (S)-4-(pyrrolidin-3-yl-sulfanyl)-phenol hydrobromide and 4-phenyl-butyraldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=2)[N:7]([CH:20]([CH3:22])[CH3:21])[CH:6]=1)=[O:4].[F:23][C:24]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].COC(C1C=C(Br)N(C(C)C)C=1)=O.ClC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=2)[N:7]([CH:20]([CH3:22])[CH3:21])[C:6]=1[CH:32]([C:30]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([F:23])[CH:31]=1)[OH:33])=[O:4]
Reactant: COC(=O)c1cc(-c2cnc(OC)nc2OC)n(C(C)C)c1
Reactant: N#Cc1ccc(C=O)cc1F
Agent: COC(=O)c1cc(Br)n(C(C)C)c1
Agent: O=Cc1ccc(Cl)cc1
Product: COC(=O)c1cc(-c2cnc(OC)nc2OC)n(C(C)C)c1C(O)c1ccc(C#N)c(F)c1

Procedure:
The title compound was prepared in analogy to the procedure described for Step D3 but 5-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step 195.3) and 2-fluoro-4-formyl-benzonitrile [101048-76-4] were used instead of 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 4-chlorobenzaldehyde respectively. The title compound was obtained as a yellow solid. tR: 1.12 min (HPLC 3); ESI-MS: tR=1.11 min, [M+H]+ 455 (LC-MS 1); TLC: Rf=0.30 (1:1 EtOAc/heptanes).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=1.O1CCCC1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>C(OCC)(=O)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:25]=[C:24]([C:26]3[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=3)[O:17][N:16]=2)=[CH:10][CH:9]=1
Reactant: ON=C(Cl)Cc1ccc(CCc2ccco2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cc(Cc3ccc(CCc4ccco4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a mixture of (4-(2-furan-2-yl-ethyl)phenyl)-acetohydroximoyl chloride (100 mg, 0.38 mmol) described in Manufacturing Example 80-1-7 and tetrahydrofuran (3 mL) were added 3-ethynyl-pyridin-2,6-diamine (25.3 mg, 0.19 mmol) described in Manufacturing Example 13-1-3 and triethylamine (0.1 mL, 0.76 mmol), which was stirred for 2 hours at room temperature. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. This organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1 then ethyl acetate) to obtain the title compound (50 mg, 72%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28]([OH:30])=O)([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:2].S(Cl)(Cl)=O.[CH3:39][O:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:33]([O:32][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28]([NH:45][C:44]2[CH:46]=[CH:47][C:41]([O:40][CH3:39])=[CH:42][CH:43]=2)=[O:30])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:34]
Reactant: COc1ccc(N)cc1
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(OC)cc2)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 0.50 g of (RS)-1-(2,2-diethoxyethyl)-3-(hydroxycarbonylmethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one in 50 ml of dichloromethane were added successively 0.140 g of 4-dimethylaminopyridine and 0.090 ml of thionyl chloride at 0° C., followed by stirring at 0° C. for 30 minutes. To the mixture were further added 0.140 g of 4-dimethylaminopyridine and 0.190 g of 4-methoxyaniline at 0° C. The resulting mixture was stirred at room temperature for 1 hour, and then washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.54 g (88%) of the title compound.
Reaction SMILES: [N:1]([C:4]1[C:19]([O:20]CC2C=CC=CC=2)=[CH:18][C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:5]=1[F:36])=[N+]=[N-].CCOCC.CS(C)=O.S1(CCCC1)(=O)=O>[Pd].[Ni].O.C(O)CC.C(O)C.CO.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C>[NH2:1][C:4]1[C:19]([OH:20])=[CH:18][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:5]=1[F:36]
Reactant: [N-]=[N+]=Nc1c(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c(Nc2ccccc2F)c1F
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Solvent: CN1CCCN(C)C1=O
Solvent: CCCO
Product: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2F)c1F

Procedure:
Benzyl 4-azido-5-(benzyloxy)-3-fluoro-2-((2-fluorophenyl)amino)benzoate can be hydrogenated catalyzed by appropriate catalyst (such as Pd/C, Pt, Ni) in the solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ester (such as ethyl acetate, methyl acetate), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methanol, ethanol, propan-1-ol and water) for some time (1-12 h, prefer 3-10 h). 4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid is obtained after conventional workup.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18].[CH2:21]([NH2:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:27][C:2]1[CH:7]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccco1
Reactant: NS(=O)(=O)c1cc(S(N)(=O)=O)c(C(Cl)=C(Cl)Cl)cc1Br
Product: NS(=O)(=O)c1cc(S(N)(=O)=O)c(C(Cl)=C(Cl)Cl)cc1NCc1ccco1

Procedure:
4-Bromo-6-trichlorovinyl-1,3-benzenedisulfonamide and furfurylamine are reacted at 70° C. for 10 hours in analogy to above procedure to give 4-furfurylamino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with m.p. 155°-155° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23].[Li]CCCC.[C:31]1([C:37]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[C:31]1([C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]([F:14])([F:13])[F:15])[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:5]3[C:22]([F:23])([F:24])[F:25])([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[OH:38])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(c1ccccc1)c1cccnc1
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1cccnc1)c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(C(F)(F)F)c2c1
Reaction time: 4 h

Procedure:
A ˜−70° C. solution of 6-bromo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (66.8 mg, 0.159 mmol, Intermediate 8, step c) in THF (0.9 mL) was treated dropwise with n-BuLi (0.12 mL, 1.59 M, 0.191 mmol) via syringe under argon over 1 min. After stirring for less than 1 min, the dark homogeneous solution was treated with a solution of phenyl(pyridin-3-yl)methanone (32.0 mg, 0.175 mmol, Aldrich) in THF (0.6 mL) over 2 min, and the resulting dark amber solution was stirred at ˜−70° C. while the cold bath was allowed to expire over 4 hours. The amber solution was then partitioned with 5 M NH4Cl (2 mL) and EtOAc (5 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by C18 HPLC (20% to 100% CH3CN, with 0.1% TFA throughout) to provide, after lyophilization, the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4) δ 8.87 (s, 1H), 8.78 (d, J=5.38 Hz, 1H), 8.47 (d, J=8.07 Hz, 1H), 8.27-8.39 (m, 2H), 7.92-8.05 (m, 2H), 7.26-7.54 (m, 10H); MS m/e 568.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[CH2:7][CH2:8][CH3:9]>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCC=O
Reactant: c1cc[nH]c1
Product: CCCC(c1ccc[nH]1)c1ccc[nH]1
Yield: 45 %

Procedure:
This was prepared as described in example 2/4, reacting the pyrrole derivative with butyraldehyde. Yield 45%.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:21].Cl.[NH2:23][CH2:24][CH2:25][O:26][NH2:27].N1C=CC=CC=1>C(O)C>[ClH:21].[ClH:21].[NH2:23][CH2:24][CH2:25][O:26][N:27]=[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCON
Reactant: O=C(CCCn1ccnc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 4-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-butanone (5.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (3.17 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 3.1 g (42%) of product, mp 207°-208° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([O:15]C)=[O:14])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=[O:14])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1cc2ccccc2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2ccccc2cc1C(=O)O

Procedure:
The methyl 3-methoxy-2-naphthoate was diluted with excess 5 percent sodium hydroxide solution and the mixture was heated at its reflux temperature until the solution was clear. The solution was acidified with hydrochloric acid to provide a precipitate which was separated by filtration. Recrystallization from benzene provided the known intermediate 3-methoxy-2-naphthoic acid, m.p. 130°-132° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]([N:8]2[C:12]3=[C:13]4[CH:19]=[CH:18][NH:17][C:14]4=[N:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:20])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1.C(N(CC)CC)C>CN1CCN(C)C1=O>[CH3:1][C@H:2]1[C@@H:7]([N:8]2[C:12]3=[C:13]4[CH:19]=[CH:18][NH:17][C:14]4=[N:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:20])[CH2:6][CH2:5][N:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=2)[CH2:3]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@@H]1CNCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Solvent: CN1CCN(C)C1=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2ccc(C#N)cn2)CC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Temperature: 160 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of rel-1-[(3R,4S)-3-methyl-4-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (20 mg) in 1,3-dimethyl-2-imidazolidinone (0.5 mL) were added 6-chloronicotinonitrile (20 mg) and triethylamine (41 μl), The mixture was stirred at 160° C. for 2 hours. The mixture was extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give rel-6-[(3R,4S)-3-methyl-4-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)-1-piperidinyl]nicotinonitrile (13 mg) as a white powder.