Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[C:10]([CH2:29][NH:30][CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[S:33]([CH3:32])(=[O:35])=[O:34])[CH2:16][CH2:15]2)=[C:10]([CH2:29][NH:30][CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NCc2ccc(F)cc2)CC1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(Cc2ccc(F)cc2)S(C)(=O)=O)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-(4-fluorobenzyl)cyclohexylamine and methanesulphonic acid chloride. Colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:29]1([N:35]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH:36]2[CH3:41])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CC(C)=O.O>[CH:29]1([N:35]2[CH2:39][CH2:38][CH:37]([NH:40][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([Cl:13])[C:10]([NH2:12])=[CH:11][C:3]=3[O:2][CH3:1])[CH:36]2[CH3:41])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC1C(N)CCN1C1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(C2CCCCC2)C1C
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
8 g of 2-methoxy-4-amino-5-chlorobenzoic acid (0.040 mole), 50 ml of acetone and 4 g of triethylamine (0.040 mole) are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The suspension is cooled and 5.5 g of isobutyl chloroformate (0.040 mole) is added drop by drop between 0° and +5° C. The reaction medium is agitated for 45 minutes with the temperature kept between 0° and +5° C., then 8 g of 1-cyclohexyl-methyl-3-aminopyrrolidine (0.044 mole) is added drop by drop. The reaction is allowed to continue for 2 hours at room temperature, then 80 ml of water is added and the acetone is expelled. The product crystallises in the residual water. It is filtered and re-dissolved in 150 ml of water and 5 ml of concentrated hydrochloric acid. The solution is filtered with charcoal and the filtrate is made alkaline with 10 ml of ammonia (density 0.91). The viscous precipitate is decanted and dissolved in 80 ml of water and 5 ml of hydrochloric acid. The product is dissolved and the hydrochloride is precipitated very rapidly. It is drained, washed with water and dried at 50° C. 10.4 g of product is obtained and is dissolved hot in 100 ml of water. The solution is rendered alkaline with 10 ml of soda lye. The oily precipitate is crystallised by cooling. It is drained, washed with water and dried in an oven at 50° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:22][CH3:23])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:31](I)[CH2:32][CH3:33]>O>[CH2:22]([N:3]1[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=[C:2]1[NH:1][CH2:31][CH2:32][CH3:33])[CH3:23]
Reactant: CCn1c(N)nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c1=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNc1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1CC
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a solution of 2-amino-3-ethyl-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (80 mg, 0.26 mmol) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 40 mg, 1.0 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of n-PrI (170 mg, 1.0 mmol) and N,N-dimethylformamide (2 ml) at 0° C. and stirred for 0.5 hour. After stirring at 50° C. for 3 hours, the mixture was cooled and diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (20:1) to give 25 mg (25%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]2SCCS2)[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2]>CO.[Ni]>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:23])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:30]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C5SCCS5)c(c34)C[C@H]2N(C)C1
Agent: [Ni]
Solvent: CO
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
7.5 ml of a Raney nickel suspension is washed four times with respectively 30 ml of methanol. Then 15 ml of methanol and thereafter a solution of 670 mg (1.5 mmol) of 1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]urea in 15 ml of methanol are added thereto. The mixture is agitated for 3 hours at room temperature and once again 7.5 ml of a Raney nickel suspension is added which has been washed, as above, previously four times with respectively 30 ml of methanol. After another 2 hours of agitation at room temperature, the catalyst is filtered off over a silica gel column and thoroughly washed with methanol. The filtrate is evaporated and the residue is crystallized from methanol/ethyl acetate, thus obtaining 170 mg of 1,1-diethyl-3-(2,6-dimethyl-8α-ergolinyl)urea (32% yield).
Reaction SMILES: NC(C1C=CC(OCCO[Si](C)(C)C)=CC=1)C(NC(C(C1C=CC=CC=1)C)C([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][CH2:17]2)=[CH:12][C:11]=1[F:19])=O)=O.N1C=CC=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.Cl>ClCCl>[CH:16]1([C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[C:11]([F:19])[CH:12]=2)[CH2:18][CH2:17]1
Reactant: CC(c1ccccc1)C(NC(=O)C(N)c1ccc(OCCO[Si](C)(C)C)cc1)C(=O)Nc1ccc(C2CC2)cc1F
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
2-{2-Amino-2-[4-(2-trimethylsilanyloxy-ethoxy)-phenyl]-acetylamino}-N-(4-cyclopropyl-2-fluorophenyl)-3-phenyl-butyramide (680 mg, 1.2 mmol) and pyridine (3 mL) were dissolved in dichloromethane (60 mL) at −78° C. To this mixture was added a solution of triphosgene (296 mg, 1 mmol) in dichloromethane (15 mL) dropwise. The mixture was allowed to slowly warm to room temperature and stirred overnight at room temperature. The mixture was cooled in an ice bath and 3 M HCl (60 mL) was added slowly and stirring was continued at 0° C. for 30 minutes. The organic layer was separated and dried over anhydrous sodium sulfate. Concentration gave 150 mg of a oily solid that was chromatographed over silica gel (65% v/v ethyl acetate in hexanes) to give N-(4-cyclopropyl-2-fluoro-phenyl)-2-{4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1yl}-3-phenyl-butyramide as a yellow solid (70 mg, 0.13 mmol, 13%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([O:13][CH2:14][C:15]#[N:16])[CH:6]=[CH:5]2.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1B(O)O.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([O:13][CH2:14][C:15]#[N:16])[CH:6]=[CH:5]2
Reactant: N#CCOc1ccc2cc(Br)ccc2c1Cl
Reactant: OB(O)c1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: N#CCOc1ccc2cc(-c3cc4ccccc4o3)ccc2c1Cl
Yield: 55.7 %

Procedure:
Following the procedure described in Step 1 of Example 1, 2-[(6-bromo-1-chloro-2-naphthyl)oxy]acetonitrile (9.7, 33 mmol) was coupled to 2-benzofuranboronic acid (6.35 g, 39 mmol), in the presence of[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (1.40 g, 1.71 mmol) and potassium carbonate (9.13 g, 66.1 mmol) in dioxane (330 mL) and water (3.3 mL). Purification by flash chromatography using 5-30% ethyl acetate in hexane and 7.5-50% ethyl acetate in hexane as eluants yielded 2-{[6-(1-benzofuran-2-yl)-1-chloro-2-naphthyl]oxy}acetonitrile as a light brown solid (6.13 g), mp 162-163° C. 1HNMR (300 MHz, DMSO-d6): δ8.55 (s, 1H), 8.15-8.25 (m, 3H), 7.65-7.75 (m, 3H), 7.6 (s, 1H), 7.25-7.4 (m, 2H), and 5.45 ppm (s, 2H).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C(Cl)(=O)C.[CH3:8][N:9]([C:13]([NH2:15])=[NH:14])[CH2:10][CH2:11][OH:12].[C:16](O)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[C:16]([O:12][CH2:11][CH2:10][N:9]([CH3:8])[C:13]([NH2:15])=[NH:14])(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CN(CCO)C(=N)N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OCCN(C)C(=N)N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 12.44 mL (175 mmol) of acetyl chloride and 35 mL of dry DCM. The flask is charged with 41.00 g (350 mmol) of Creatinol and 175 mL of dry DCM, and cooled with an ice-water bath to about 0° C., under a nitrogen atmosphere. The acetyl chloride solution is then added slowly with stirring, over a period of 15 minutes, to the Creatinol solution. The solution is stirred for another 10 minutes, after which 15.38 g (60 mmol) of Palmitic acid is added in one portion and the reaction is slowly heated to about 65° C. for about 10 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 2/5) to yield pure 2-(1-methylguanidino)ethyl palmitate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:49][CH3:50])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([O:44]COC)([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH3:48])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][C:13]=1[F:52]>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:49][CH3:50])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([OH:44])([C:40]([F:41])([F:43])[F:42])[C:36]([F:38])([F:37])[F:39])=[C:29]([CH3:48])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][C:13]=1[F:52]
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
Dichloromethane (1.5 mL) and trifluoroacetic acid (0.153 mL) were added to (4′-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 78-(1); 41 mg, 0.063 mmol), and the mixture was stirred at room temperature for one day. The reaction solution was directly concentrated under reduced pressure and azeotropically distilled with toluene. The residue was purified by preparative TLC (hexane/ethyl acetate=5/1) to give the title compound (30.1 mg, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:14])[CH3:2].C([N-]C(C)C)(C)C.[Li+].CON(C)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)=[O:27]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH2:14][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)=[O:27])[CH3:2]
Reactant: CON(C)C(=O)c1cccc(C)n1
Reactant: CCOc1ccc2nccc(C)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc2nccc(CC(=O)c3cccc(C)n3)c2c1
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To a solution of 6-ethoxy-4-methyl-quinoline (360 mg, 2.0 mmol) in THF at −78° C. add 1.5M lithium diisopropylamide (4.6 ml, 7.0 mmol) dropwise and stir for 1 hour. 6-Methyl-pyridine-2-carboxylic acid methoxy-methyl-amide (430 mg, 2.4 mmol) is then added, and the mixture stirred for 30 minutes at −78° C. before quenching with 1N HCl (5 ml). Neutralize with saturated aqueous NaHCO3 and extract with EtOAc (3×50 ml). The organic phase is then dried with MgSO4 and concentrated in vacuo. The crude product was chromatographed on silica gel (elute with 50/50 Hexane/EtOAc) to give 120 mg (20%) of the title compound. MS ES+ m/e 307.1 (M+1).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([OH:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:30][C:31](Cl)=[O:32]>CCOCC>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:12][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:26][CH2:30][C:31]1=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: OC(CCNCc1ccccc1)(COc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C1COC(COc2ccccc2)(c2ccccc2)CCN1Cc1ccccc1
Reaction time: 2 h

Procedure:
60 g (0.17 mole) of the N-benzyl-3-hydroxy-3-phenyl-4-phenoxybutylamine obtained as described in (c) were dissolved in 600 ml of ether, 150 ml of 2N sodium hydroxide solution were added and 22.6 g (0.2 mole) of chloroacetyl chloride in 50 ml of ether were added dropwise at room temperature. The mixture was refluxed for 30 minutes, after which the ether phase was separated off and dried, and 150 ml of isopropanol were added. To this solution was added dropwise, in the course of 30 minutes, a solution of 3.4 g of sodium in 375 ml of isopropanol, which solution had been diluted beforehand with 1,200 ml of hexane. The mixture was stirred for 2 hours and then left to stand overnight, after which the solvent was distilled off, water was added and the product was extracted with chloroform. The extract was dried and evaporated down to give 4-benzyl-3-oxo-7-phenyl-7-phenoxymethyl-hexahydro-1,4-oxazepine, which was processed further in crude form.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:26]([NH:25][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:27])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
A mixture of 0.35 g (1.4 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline 0.185 (1.6 mmol) of phenylisocyanate and 10 ml of tetrahydrofuran is stirred at room temperature for 3 days. The reaction mixture is filtered and the solid collected is triturated in ether to yield 0.35 g (68%) of the title compound as an off white solid: m.p.>260° C.; m/e 299.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:29])([F:28])[F:27])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16]C(=O)C3C=CC(Cl)=CN=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1.Cl[C:31]1[N:32]=[CH:33][C:34]([F:43])=[C:35]2[C:40]=1[N:39]=[CH:38][C:37]([C:41]#[N:42])=[CH:36]2.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:27])([F:29])[F:28])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:31]3[N:32]=[CH:33][C:34]([F:43])=[C:35]4[C:40]=3[N:39]=[CH:38][C:37]([C:41]#[N:42])=[CH:36]4)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1
Reactant: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: N#Cc1cnc2c(Cl)ncc(F)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: C[C@@]1(c2cc(Nc3ncc(F)c4cc(C#N)cnc34)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 100 °C
Yield: 45 %

Procedure:
To a solution of (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (6a, 0.076 g, 0.260 mmol) and 8-chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile (intermediate 17, 0.065 g, 0.312 mmol) in 2-propanol (2.6 ml) was added 4-methylbenzene sulfonic acid (monohydrate, Fluka, 0.099 g, 0.520 mmol). The reaction mixture was heated to 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between DCM and aqueous saturated sodium bicarbonate. The aqueous layer was backextracted with DCM. The combined organic extracts were washed with brine and dried over sodium sulfate. The filtrate was concentrated and the residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min. The product containing fractions were combined and neutralized with aqueous sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (0.054 g, 0.117 mmol, 44.8% yield) as yellow solid. MS m/z=464.0 [M+H]+. Calculated for C20H14F5N7O: 463.4
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=NC2N(O)N=NC=2C=1>CCOC(C)=O.CN(C=O)C>[F:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][C:24]2[CH:25]=[C:26]([NH:27][C:14]([C:11]3([CH3:17])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[O:16])[CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: Nc1cccc(Oc2ccc(F)cc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CC1
Temperature: 80 °C

Procedure:
1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (243 mg, 1.0 mmol), 3-(4-fluorophenoxy)aniline (203 mg, 1.0 mmol), DCC (206 mg, 1.0 mmol), and HOAt (138 mg, 1.01 mmol) were combined in EtOAc (50 mL) and DMF (5 mL). The reaction mixture was heated at 80° C. for 20 hours. Most of the EtOAc was evaporated, resulting in precipitation of a solid, which was removed by filtration. The filtrate was diluted with EtOAc, washed with 1 N aq. HCl, water, and brine, dried, and concentrated under vacuum to give the title compound. MS (ES+) [M+H]+=429.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH:26]1[C@H:32]2[N:33]([CH3:34])[C@H:29]([CH2:30][CH2:31]2)[CH2:28][CH2:27]1>>[C@@H:29]12[N:33]([CH3:34])[C@@H:32]([CH2:31][CH2:30]1)[CH:26]([NH:25][C:10]([C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=1)=[O:12])[CH2:27][CH2:28]2
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CN1[C@H]2CCC(N)[C@@H]1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN1[C@H]2CCC(NC(=O)c3n[nH]c4ccccc34)[C@@H]1CC2
Yield: 18 %

Procedure:
1H-Indazole-3-carboxylic acid (9.73 g, 60 mmol), 1,1'-carbonyldiimidazole (9.74 g, 60 mmol), and 4-aminotropane (8.42 g, 60 mmol) were converted to the title compound by the procedure of Preparation 7, Step 2 to give 3.02 g. Yield: 18%. m.p. 222° C.-224° C. EA calculated for C16H20N4O: C, 67.58; H, 7.09; N, 19.70. Found: C, 67.65; H, 7.25; N, 19.75. MS(FD) M+ 284.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21](=O)[CH3:22])=[C:6]([CH3:20])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([Cl:19])[CH:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:24][NH2:25]>>[Cl:19][C:12]1[CH:11]=[C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:21]([CH3:22])=[N:24][N:25]=[C:1]3[CH3:2])=[C:6]2[CH3:20])[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][CH3:18]
Reactant: NN
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)cc1Cl
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)cc1Cl

Procedure:
Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(3-chloro-4-ethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 6-(3-Chloro-4-ethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as yellow solid: 1H NMR (CD3OD, 500 MHz) δ 7.47 (s, 1H), 7.32 (d, 1H), 7.25 (d, 1H), 4.27 (q, 2H), 2.79 (s, 6H), 2.48 (s, 6H), 1.53 (t, 3H); MS (ESI) 330 (M+H)+.
Reaction SMILES: Cl.[CH:2]([N:5]([CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][CH2:10]1)[CH2:6][CH2:7][CH3:8])([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH:2]([N:5]([CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11](=[O:33])[CH2:10]1)[CH2:6][CH2:7][CH3:8])([CH3:3])[CH3:4]
Reactant: CCCN(C(C)C)C1CSc2cccc(-c3ccccc3)c2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCN(C(C)C)C1Cc2c(-c3ccccc3)cccc2S(=O)C1

Procedure:
3-(N-Isopropyl-N-n-propylamino)-5-phenylthiochroman hydrochloride (310 mg, 0.86 mmol) was dissolved in 6 mL chloroform and to the cooled solution (ice-bath) was m-chloroperbenzoic acid (348 mg, 1.72 mmol) added in one portion.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[F:6][C:7]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][C:12]=1F.C(N(CC)C(C)C)(C)C>>[F:6][C:7]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][C:12]=1[N:3]1[CH2:4][CH2:5][S:1][CH2:2]1
Reactant: C1CSCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCSC2)c(F)c1
Yield: 23.9 %

Procedure:
Using the same general procedure as step 1, of Example 1, 4.092 g (45.90 mmol) thiazolidine was treated with 4.1 mL (37.03 mmol) 3,4-difluoronitrobenzene and 10.0 mL (57.41 mmol) N,N diisopropylethyl amine to provide 2.020 g (24%) of the title compound as an orange solid. Recystallization from methylene chloride/hexane provided an analytical sample with a melting point of 94°-95° C.