Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccccn4)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccccn4)cc2)CCN3CCC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.40 g) was dissolved in methylene chloride (12 ml), m-chloroperbenzoic acid (111 mg) was added to the mixture at 0° C., and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 193) (181 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH3:9])=[C:4]([CH2:10][CH2:11][CH2:12][CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[CH2:10]([C:4]1[C:5]([CH3:9])=[C:6]([Cl:16])[N:7]=[C:2]([NH2:1])[N:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc(N)nc(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nc(N)nc(Cl)c1C

Procedure:
By reacting 2-amino-6-butyl-5-methylpyrimidine-4-ol (0.82 g, 4.52 mmol) and phosphorous oxychloride (10 ml), there was obtained the object compound (720 mg).
Reaction SMILES: [CH:1]([NH2:5])([CH2:3][CH3:4])[CH3:2].Cl[CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11]>>[CH:1]([NH:5][CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N
Reactant: CC(O)OCCCl
Product: CCC(C)NCCOC(C)O
Yield: 60.6 %

Procedure:
In the manner described in Example 8, 131 g of secondarybutylamine and 93 g of 2-chloroethoxyethanol yielded 73 g of secondarybutylaminoethoxyethanol having a b.p. 120° C. (10 mm). Analysis calculated for C8H19NO2 : %N, 8.70: Found: %N, 8.45.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[C:13]([F:20])([F:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CS(C)=O.[Cu]>[CH2:17]([O:16][C:14](=[O:15])[C:13]([F:20])([F:19])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:18]
Reactant: Brc1ccc2ccccc2n1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc2ccccc2n1
Temperature: 55 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
A mixture of 2-bromoquinoline (5.0 g, 24.0 mmol), ethyl 2-bromo-2,2-difluoroacetate (5.8 g, 28.8 mmol) and copper power (3.5 g, 55.2 mmol) in DMSO (20 ml) was stirred at 55° C. for 5 hours. The solid was filtered off and water (100 ml) and EA (150 ml) were added. The organic layer was separated and evaporated and concentrated to give the title product (4.2 g, 70%) which was used for the next step without further purification. LC-MS (ESI+): m/e 252 (M+H)+, Rt: 0.934 min/2.5 min.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[N+:6]([C:9]1[O:13][C:12]([C:14]2[C:18]([CH:19]=[N+:20](C)C)=[CH:17][N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:15]=2)=[CH:11][CH:10]=1)([O-:8])=[O:7].C([O-])(=[O:31])C.[Na+].Cl.NO.CN(C)C=O>O>[N+:6]([C:9]1[O:13][C:12]([C:14]2[C:18]([CH:19]=[N:20][OH:31])=[CH:17][N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:15]=2)=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: CC(=O)[O-]
Reactant: C[N+](C)=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2nn(-c3ccccc3)cc2C=NO)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Add 2.0 g of [3-(5-nitro-2-furyl)-1-phenylpyrazol-4-ylmethylene]dimethylammonium perchlorate, 0.42 g of anhydrous sodium acetate and 0.36 g of hydroxylamine hydrochloride to 11 ml of dimethylformamide. Stir the resulting admixture for 2 hours at room temperature before adding 30 ml of water dropwise thereto to precipitate the title compound for a 95% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehydeoxime [m.p. 199° to 201° C (with decomposition)].
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C@H:23]2[C@H:28]([O:29]CC3C=CC=CC=3)[C@@H:27]([O:37]CC3C=CC=CC=3)[C@H:26]([O:45]CC3C=CC=CC=3)[C@@H:25]([CH2:53][O:54]CC3C=CC=CC=3)[O:24]2)=[CH:19][C:3]=1[CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:10]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[O-].[Na+].[H][H]>C(OC(=O)C)(=O)C.CO>[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([CH:23]2[CH:28]([OH:29])[CH:27]([OH:37])[CH:26]([OH:45])[CH:25]([CH2:53][OH:54])[O:24]2)=[CH:19][C:3]=1[CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(C#Cc2ccccc2)nn1
Agent: C[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: OCC1OC(c2ccc(Cl)c(Cc3ccc(C#Cc4ccccc4)nn3)c2)C(O)C(O)C1O
Temperature: 25 °C
Yield: 20 %

Procedure:
To a solution of 3-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)-6-(phenylethynyl)pyridazine (0.5 mmol) from step 1 at −30° C. in acetic anhydride (10 mL) was slowly added a solution of trimethylsilyl trifluoromethanesulfonate (0.73 mL, 4.0 mmol) in acetic anhydride (5 mL). The resulting mixture was stirred with gradual warming to ambient temperature over 15 h, cooled to 0° C., and quenched with saturated sodium bicarbonate. After dilution with ethyl acetate, the organic layer was washed with sodium bicarbonate and brine prior to drying over magnesium sulfate. Filtration and removal of volatiles under reduced pressure yielded peracetylated compound as a brown amorphous solid. Deacetylation was achieved by addition of sodium methoxide (25 wt % in methanol, 1 mL) to a solution of this residue in methanol (10 mL). The reaction mixture was stirred at ambient temperature for 2 h. Amberlite® IR120 hydrogen form was then added to neutralize the reaction mixture. The resin was filtered off and the filtrate was concentrated in vacuo. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (41 mg, 0.10 mmol, 25%) as a white solid.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[Br:1][C:8]1[CH:9]=[C:4]([Cl:3])[C:5]([OH:10])=[N:6][CH:7]=1
Reactant: Oc1ncccc1Cl
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
10.5 ml (203.0 mmol) of bromine are added dropwise at 0° C. to 23.9 g (184.5 mmol) of 3-chloro-2-hydroxypyridine in 240 ml of dimethylformamide, and the mixture is stirred at room temperature for 2 hours. 200 ml of water are subsequently added, and 30 g of sodium sulfite in 100 ml of water are added dropwise. After 15 minutes, the mixture is extracted three times with 200 ml of dichloromethane in each case, the combined organic phases are dried over sodium sulfate and filtered, and the filtrate is evaporated to dryness, giving 36.58 g of 5-bromo-3-chloro-2-hydroxypyridine. ##STR13## m.p.: 168° C. (decomp.)
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[N:19][N:20]([C:22]2[N:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=2[CH3:31])[CH:21]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:25]3[CH:26]=[N:27][C:22]([N:20]4[CH:21]=[C:17]([Cl:16])[CH:18]=[N:19]4)=[C:23]([CH3:31])[CH:24]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1-n1cc(Cl)cn1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1-n1cc(Cl)cn1
Yield: 59 %

Procedure:
The title compound is prepared in 59% yield (160 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-1) and 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanamine hydrochloride (200 mg, 0.72 mmol, Amine-45, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][NH:16][C:17]2=[O:20])=[CH:12][CH:11]=1>CC#N>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:1])=[CH:15][NH:16][C:17]2=[O:20])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Solvent: CC#N
Product: O=c1[nH]cc(Cl)c2ccc(Br)cc12
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A solution of N-chlorosuccinimide (4.13 g, 31 mmol) in MeCN (50 mL) was added dropwise to a stirred solution of 7-bromo-1-(2H)-isoquinolone (6.6 g, 29.5 mmol) in MeCN (150 mL) which was heating under reflux. The mixture was heated under reflux for an additional 3 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 7-bromo-4-chloro-1(2H)-isoquinolone (6.72 g, 26.0 mmol) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]=[O:13]>>[CH:12]([C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])=[O:13]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=O
Product: COC(=O)c1ccc(O)c(C=O)c1
Yield: 46.3 %

Procedure:
Proceeding as in Reference 8, but substituting methyl 4-hydroxybenzoate (30.4 g, 0.20 mol, 1.0 eq.) and paraformaldehyde (42.0 g, 1.40 mol, 7.0 eq.), gave methyl 3-formyl-4-hydroxybenzoate (16.7 g) as a white solid.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(C(C)C)C(C)C)C.ClC(OC(Cl)C)=O>C(Cl)Cl>[NH:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc(C2CCN(C)CC2)c2ccccc12
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C2CCNCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of D9 (0.39 g, 1.4 mmole) in DCM (30 ml) was treated with iPr2EtN (0.26 g, 2 mmole) followed by 1-chloroethyl chloroformate (0.29 g, 2 mmole) and stirred at room temperature for 3 h, then concentrated under vacuum and the residue treated with MeOH (30 ml) and heated under reflux for 1 h. The mixture was allowed to cool and the solid filtered off, washed with Et2O and dried. This was treated with 10% Na2CO3 solution, extracted with DCM and the extract dried and concentrated under vacuum to afford the title compound as a colourless oil (0.33 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([NH:30][C:31](OC2C=CC=CC=2)=[O:32])[C:23](=[CH:28][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:31]([NH:30][C:22]2[CH:21]=[C:20]([Cl:19])[CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[O:32])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1O
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Yield: 100.9 %

Procedure:
1.0 g (3.66 mmol) of 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and 1.12 g (3.66 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 7 to obtain 1.79 g (yield 100%) of methyl 2-{[(4-t-butoxycarbonyl-3-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 1.57 (9H, s), 3.87 (3H, s), 7.14 (1H, d), 7.40–7.45 (2H, m), 7.85 (1H, d), 7.92 (1H, d), 8.32 (1H, d), 10.13 (1H, s), 10.82 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[NH:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:17]=3)[NH:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(F)c2c1CC(C)(C)C(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(F)c2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-8-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (6.0 g, 15.3 mmol), morpholine (13.3 mL, 153 mmol), copper(I) iodide (874 mg, 4.6 mmol), N,N-dimethylglycine hydrochloride (1.3 g, 9.2 mmol) and potassium carbonate (8.5 g, 61.2 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (4.8 g, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C23H27FN2O3 (M+H)+: 399.48, observed: 399.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[CH:5]2.C([Sn](CCCC)(CCCC)[C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:19][CH:18]=1)CCC>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:17]3[S:21][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[N:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Brc1ccc2nnccc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc3nnccc3c2)s1
Yield: 73.1 %

Procedure:
The title compound (0.24 g, 60%) was synthesized in a manner similar to that described in Example 253 from 6-bromocinnoline (0.25 g, 1.0 mmol) and tert-butyl 5-(tributylstannyl)thiazol-2-ylcarbamate (0.90 g, 1.5 eq). LCMS (API-ES) m/z (%): 329.4 (100%, M++H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][CH2:38][NH2:39]>>[C:2]1([C:1]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([CH2:22][NH:39][CH2:38][CH2:37][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)[CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:27]([F:29])([F:28])[F:30])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: NCCc1ccccn1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(CNCCc2ccccn2)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 2-pyridin-2-yl-ethylamine according to the procedure of Example 66. MS m/z 512.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[NH:3]1.[H][H]>[Pt]=O.C(O)C>[CH3:1][N:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])[NH:3]1
Reactant: [H][H]
Reactant: CN1C=NN(c2cccc([N+](=O)[O-])c2)N1
Agent: O=[Pt]
Solvent: CCO
Product: CN1C=NN(c2cccc(N)c2)N1
Yield: 91.9 %

Procedure:
The nitro group was reduced as follows: To a 250 ml Parr bottle were added 800 mg (3.9 mmol) of 3-(1-methyltetrazol-3-yl)nitrobenzene, 200 mg platinum oxide, and 75 ml ethanol. The reaction was pressurized with 45 p.s.i. hydrogen for 1 hour, then catalyst removed by filtration, and the solvent evaporated to afford 635 mg (93.0%) of a white solid, mp 93°-95° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=[O:17])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:27][C:28](O)([CH3:31])[CH2:29][OH:30]>>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH2:16][O:17][C:28]([CH3:31])([CH3:27])[CH2:29][OH:30])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CC(C)(O)CO
Product: CC(C)(CO)OCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F

Procedure:
Using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 as a starting material, and 2-methyl-propane-1,2-diol obtained in Step A instead of ethylene glycol used as a reagent in Step G of Example 1, synthesis similar to that in Step G of Example 1 was performed. The resultant cyclic acetal was subjected to reduction condition similar to that in Step H of Example 1 to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22](O)=[O:23])[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]([CH2:49][NH2:50])[OH:48].O>ClCCl>[OH:48][CH2:47][CH2:49][NH:50][C:22]([C:9]1[C:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:14][C:15]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=2[CH:8]=1)=[O:23]
Reactant: NCCO
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c3c(c(C(=O)NCCO)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Reaction time: 64 h
Yield: 15.6 %

Procedure:
To a suspension of 0.3 g (0.93 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred for 64 h at room temperature. 284 μl (4.7 mmol) Ethanolamine were added and the mixture was stirred for 24 h at room temperature. The reaction was poured into water and the precipitate filtered off. The residue was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to afford 53 mg (17%) of the title compound as a yellow solid. m.p. 228°-229° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](=O)[CH3:18])[CH:15]=2)[CH:10]=[C:9]1[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[N:22][C:21]=1[O:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[CH3:18])[CH:15]=2)[CH:10]=[C:9]1[C:20]1[CH:25]=[C:24]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[N:23]=[N:22][C:21]=1[O:32][CH3:33])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(C(C)=O)cc2n1C(=O)OC(C)(C)C
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(C(C)N3CCN(C)CC3)cc2n1C(=O)OC(C)(C)C
Temperature: 65 °C

Procedure:
180 mg resin bound (2.57 mmol/g) sodium cyano borhydride are added to a solution of 80 mg 6-acetyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester, 22 mg N-methyl-piperazine and 0.062 ml acidic acid and the mixture stirred over night at 65° C. The crude product is isolated by filtration and evaporation of the solvent and is used without further purification.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[N:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17].[BH4-].[Na+].O>CO.C(Cl)Cl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][NH:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17]
Reactant: CC(C)(C)S(=O)N=Cc1ccc2oc3ccccc3c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)S(=O)NCc1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of N-(dibenzo[b,d]furan-2-ylmethylene)-2-methylpropane-2-sulfinamide (2.260 g; 7.55 mmol) in anh. MeOH (27 ml) and anh. DCM (57 ml) was treated with NaBH4 (343 mg; 9.06 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 10 min. Water and DCM were added, and the organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording N-(dibenzo[b,d]furan-2-ylmethyl)-2-methylpropane-2-sulfinamide as a yellow solid. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 302.01 g/mol.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[CH2:3][N:4]([C:12]1[S:13][C:14]([C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[N:20][N:21]=[CH:22]3)=[N:15][N:16]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=1)[CH2:3][NH:4][C:12]1[S:13][C:14]([C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[N:20][N:21]=[CH:22]3)=[N:15][N:16]=1
Reactant: CC(C)(C)OC(=O)N(C[C@@H](N)Cc1ccc(C(F)(F)F)cc1)c1nnc(-c2cccc3cnncc23)s1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1nnc(-c2cccc3cnncc23)s1)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a 50 mL round bottom flask was added tert-butyl (S)-2-amino-3(4-(trifluoromethyl)phenyl)propyl(5-(phthalazin-5-yl)-1,3,4-thiadiazol-2-yl)carbamate (0.025 g, 0.0476 mmol) DCM (5 mL) and TFA (5 mL). The resulting solution was stirred for 30 minutes and evaporated. The residue was dissolved in EtOAc (100 mL), washed with a mixture of aqueous saturated sodium bicarbonate plus 5% 5N NaOH, and saturated sodium bicarbonate (2×). The organic layer was dried over sodium sulfate and evaporated to provide N—((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(phthalazin-5-yl)-1,3,4-thiadiazol-2-amine as a tan solid (15 mg, 75%). LCMS (M+H) 431.2 calc. for C20H18F3N6S 431.1. 1H NMR (400 MHz, CDCl3): δ ppm 2.83 (dd, J=14.28, 8.61 Hz, 2H) 3.10 (dd, J=14.28, 4.50 Hz, 1H) 3.71 (m, 1H) 4.22 (d, 2H) 7.12-7.15 (d, 2H) 7.39 (d, J=8.22 Hz, 1H) 7.60 (d, 1H) 8.07 (m, J=1.17 Hz, 1H) 8.11 (d, 1H) 8.17 (d, 1H) 9.70 (s, 1H) 9.87 (s, 1H). 2H not detected.