Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]([NH2:8])=[C:6](I)[N:5]=[CH:4][N:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[I:1][C:2]1[C:7]([NH2:8])=[C:6]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1c(I)ncnc1I
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Nc1c(I)ncnc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
4,6-Diiodopyrimidin-5-amine (2.2 g) was dissolved in 1-methyl-2-pyrrolidone (11.5 mL), phenol (656 mg) and potassium carbonate (964 mg) were added, and the mixture was stirred at 100° C. for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and saturated brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80) to give the title compound (2.0 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[CH3:1][C:2]1[C:3](/[CH:4]=[CH:20]/[N+:17]([O-:19])=[O:18])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: C[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1C
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cccc(/C=C/[N+](=O)[O-])c1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-3-(methyloxy)benzaldehyde (available from Allichem Product List; 20 g; 133 mmol) in nitromethane (400 ml) was added ammonium acetate (6.16 g; 80 mmol) and the resulting orange mixture was stirred for 1 h at 100° C. then cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (×2) and brine, and the organic layers washed with brine, dried (MgSO4) and concentrated in vacuo. Trituration with dichloromethane/ether gave the title compound as a yellow solid (6.6 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][CH:48]([F:58])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[N:51][N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:58][CH:48]([F:47])[C:49]1[N:53]2[CH2:54][CH2:55][N:56]([C:4]([C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])=[O:6])[CH2:57][C:52]2=[N:51][N:50]=1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: FC(F)c1nnc2n1CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(nnc2C(F)F)C1
Reaction time: 12 h
Yield: 19.1 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (685 mg, 2.30 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.10 g, 3.45 mmol), crude 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 23d (400 mg, 2.30 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.90 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-[3-(difluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 23 (200 mg, yield 20.0%) as a white solid.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].N[C:9]1[C:10]([C:16]([NH2:18])=[O:17])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1>C(Cl)Cl>[F:1][C:9]1[C:10]([C:16]([NH2:18])=[O:17])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1
Reactant: F[B-](F)(F)F
Reactant: NC(=O)c1ncc(Br)cc1N
Agent: N#[O+]
Solvent: ClCCl
Product: NC(=O)c1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Nitrosonium tetrafluoroborate (300 mg, 2.58 mmol) was added to a suspension of 3-amino-5-bromopyridine-2-carboxamide (466 mg, 2.15 mmol) in DCM (30 mL) and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and toluene (30 mL) was added and the mixture heated to reflux for 2 h. After cooling to room temperature the solvent was removed in vacuo and the crude slurried in DCM (10 mL), filtered, washed with DCM and dried in vacuo at 40° C. to give 3-fluoro-5-bromopyridine-2-carboxamide which was used directly without further purification.
Reaction SMILES: C1(O)C=CC=CC=1.[F:8][C:9]([F:27])([F:26])[C:10]1[N:14]2[CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.BrC1C=N[C:32]2N([C:35]([CH:38]([CH3:40])C)=[N:36][N:37]=2)C=1.C([O-])([O-])=O.[Cs+].[Cs+].C(#N)CCC>>[N:37]1[CH:32]=[CH:40][CH:38]=[C:35]([O:25][C:22]2[CH:21]=[CH:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:14]([C:10]([C:9]([F:8])([F:26])[F:27])=[N:11][N:12]=4)[CH:15]=3)=[CH:24][CH:23]=2)[N:36]=1
Reactant: Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Reactant: CC(C)c1nnc2ncc(Br)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: CCCC#N
Product: FC(F)(F)c1nnc2ccc(-c3ccc(Oc4cccnn4)cc3)cn12
Temperature: 140 °C

Procedure:
In a sealable flask, a suspension of the phenol, 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenol, prepared as described in Example 1 (47 mg, 0.17 mmol), heteroaryl chloride (39 mg, 0.34 mmol), Cs2CO3 (111 mg, 0.34 mmol), and butyronitrile (1 mL) is heated to 140° C. overnight. The reaction is concentrated and purified by RP-HPLC to afford the desired product, 6-(4-(pyridazin-3-yloxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:21]([O-])=[O:22])([CH3:20])[CH2:13][CH2:14][CH:15]1[O:19][CH2:18][CH2:17][O:16]1.C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:21]([C:12]([CH3:20])([CH3:11])[CH2:13][CH2:14][CH:15]1[O:16][CH2:17][CH2:18][O:19]1)[O-:22]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(CCC1OCCO1)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(CCC1OCCO1)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.7 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (290.6 mg, 2.04 mmol), 2-(3-methyl-3-nitrobutyl)-1,3-dioxolane (776.8 mg, 4.11 mmol) and zinc (402.7 mg, 6.16 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.69 ml, 12.0 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature and stirred for 10 hours and let stand overnight. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=4/1-1/1) to give the title compound (419.4 mg; 69%).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH:1]1([NH:7][C:8]2[S:9][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)NC1CCCCC1
Solvent: CCO
Product: CCOC(=O)c1csc(NC2CCCCC2)n1

Procedure:
The reaction described in Preparation 42 was repeated, but using 17 g of cyclohexylthiourea, 22 g of ethyl bromopyruvate and 200 ml of ethanol, giving the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][C:37](=[O:39])[CH2:36][C:35]1=[O:40]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:34]4[C:35](=[O:40])[CH2:36][C:37](=[O:39])[CH:38]=4)[CH2:21]3)[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C1CC(=O)C(=O)C1
Reactant: C[C@@H](O[C@H]1CC[C@@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3=O)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from (3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (Example 6) and cyclopentane-1,2,4-trione according to the procedure of Example 7. MS: (MH)+ 570.0
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1)(=[O:23])[CH3:22].C(N(CC)CC)C>CS(C)=O>[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:26]1)(=[O:23])[CH3:22]
Reactant: CC(=O)NC1CCCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)NC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(566 mg), 3-acetamidopiperidine (300 mg), triethylamine (220 mg) and dimethylsulfoxide (10 ml) was heated at 100° C. for 2 hours with stirring. Thereafter the mixture was cooled to room temperature and ice water was added thereto. The precipitated crystalline was filtered off andwashed with methanol-ether to give 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (540 mg) (m.p. 280°-282° C., recrystallized from methanol). The product (405 mg) obtained in the above manner was suspended in 6N hydrochloric acid (5 ml) and heated at 100° C. for 2.5 hours with stirring. The reaction mixture was further processed in a similar manner to step (b) of Example 1 to afford hydrochloride of 7-(3-aminopiperidinly-1)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. The physical properties of this product were identical with those of the compound provided in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[Li+].[CH3:21]C([N-]C(C)C)C.IC>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[CH3:21]
Reactant: COC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
A solution of bis-(4-chloro-phenyl)-acetic acid methyl ester (1.19 g, 4.0 mmol) in THF (20 ml) was cooled to −78° C. under nitrogen. A solution of LDA (3.0 mL, 6.0 mmol, 2M in heptane/THF/ethylbenzene) was added over 5 minutes, then after a further 20 minutes, iodomethane (0.63 ml, 10.1 mmol) was added. After 4 hours the reaction was quenched by the addition of saturated ammonium chloride solution and allowed to warm to room temperature then concentrated in vacuo to remove organic solvents. The mixture was diluted with ethyl acetate/petrol 1:4 and washed with saturated ammonium chloride solution then brine, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with an ethyl acetate/petrol gradient (1% to 2%), to afford the title compound as a colourless oil (210 mg, 17%); LCMS (PS-B3) Rt 4.01 min. No Ionisation. 1H NMR (CDCl3) δ 1.88 (3H, s), 3.73 (3H, s), 7.11-7.14 (4H, m), 7.26-7.30 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:15]2[S:24][C:23]3[C:22]4[CH:25]=[CH:26][C:27]([C:29]([OH:31])=O)=[CH:28][C:21]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1.Cl.[CH3:33][NH2:34]>>[NH2:1][C:2]1[N:3]=[C:4]([C:15]2[S:24][C:23]3[C:22]4[CH:25]=[CH:26][C:27]([C:29]([NH:34][CH3:33])=[O:31])=[CH:28][C:21]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1
Reactant: CN
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)n(-c2ccc(F)cc2F)n1
Agent: Cl
Product: CNC(=O)c1ccc2c(c1)OCCc1cc(-c3nc(N)nn3-c3ccc(F)cc3F)sc1-2

Procedure:
Similarly to as described in General Procedure D, 2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylic acid was reacted with methylamine hydrochloride to give 127 as a colorless solid after reverse phase HPLC (140 mg). LCMS: 454.1
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[S:3])[NH:1]2)[CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17]
Reactant: O=C1CNC(=S)N1
Reactant: N#Cc1cc(C=O)cc(O)c1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: N#Cc1cc(C=C2NC(=S)NC2=O)cc(O)c1O
Temperature: 100 °C

Procedure:
A solution containing 0.58 g of thiohydantoin, 0.82 g of 3,4-dihydroxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with ether. Yield 0.51 g, mp 210-213° C.
Reaction SMILES: BrC1C=C[C:5]2[S:10]CC=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[C:6]=2C=1.[CH3:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][CH:25]=1.BrC1C=C2C(=CC=1)OC(=O)CS2.BrC1C=CC2SCCC(O)(C3C=CC=C(C)C=3)C=2C=1.[NH3:59]>C1(C)C=CC=CC=1.CN(C)C=O.C(OCC)C>[C:19]([C:20]1[CH:25]=[CH:24][C:23]2[S:10][CH2:5][CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[C:22]=2[CH:21]=1)#[N:59]
Reactant: Cc1cccc(C2=CCSc3ccc(Br)cc32)c1
Reactant: Cc1cccc([Mg]Br)c1
Reactant: N
Agent: Cc1cccc(C2(O)CCSc3ccc(Br)cc32)c1
Agent: O=C1CSc2cc(Br)ccc2O1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccc(C2=CCSc3ccc(C#N)cc32)c1
Reaction time: 6 h

Procedure:
6-Bromo-4-(3-methylphenyl)-2H-1-benzothiopyran (31.89 g., 0.10 mole) [prepared by addition of 3-methylphenylmagnesium bromide to an ethyl ether solution of 6-bromo-4-thiachromanone and subsequent dehydration of the resulting 6-bromo-4-hydroxy-4-(3-methylphenyl)-3,4-dihydro-2H-1-benzothiopyran] is added dropwise to a stirred mixture of cuprous cyanide (12.5 g., 0.14 mole) and 35 ml. dimethylformamide at 160° C. Heating is continued at 160°-170° C. for six hours. The cooled reaction mixture is added to 100 ml. 10% (by weight) aqueous ammonia. Toluene, 100 ml., is added and the resulting mixture stirred for 30 minutes and filtered. The filtrate is extracted with ethyl ether, the organic layers separated and the combined extracts washed with dilute ammonium hydroxide, water, dilute hydrochloric acid and finally with water again. The extracts are dried (MgSO4) and evaporated to dryness to afford the crude title compound which is purified by column chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:33](I)[C:34]([CH3:37])([CH3:36])[CH3:35]>C(OCC)(=O)C.O>[Br:20][C:17]1[CH:18]=[C:19]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([O:21][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:8]=3)[O:13][C:14]2=[N:15][CH:16]=1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)cnc1O2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A 350 mL sealable flask was charged with (R)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (12.10 g, 34.8 mmol) and DMF (99 mL, 34.8 mmol). To this solution was added cesium carbonate (28.3 g, 87 mmol). The resulting brown slurry was stirred at rt for 3 minutes before neopentyl iodide (9.21 mL, 69.5 mmol) was added in one portion. The reaction vessel was sealed and heated at 100° C. After heating for 4 hours another 1 mL of neopentyl iodide was added and heating at 100° C. was continued for another 1 hour at which point the reaction was allowed to cool to room temperature. The reaction was diluted with ethyl acetate (500 mL) and poured into water (2000 mL) before being transferred into a separatory funnel containing ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water and then brine. The aqeuous layer was combined with the above brined wash and was then extracted with DCM (2×500 mL). The organic layers were washed with water and then brine. All of the organigs were combined, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown foam that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (330 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (R)-3-bromo-7-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([N:29](CC)CC)C.COC1C=CC(CN)=CC=1>CS(C)=O>[NH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:29])[N:7]=2)=[CH:10][CH:11]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Agent: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: Nc1nccc(Oc2ccc(N)c3ccccc23)n1
Temperature: 95 °C

Procedure:
To a solution of tert-butyl 4-(2-chloropyrimidin-4-yloxy)naphthalen-1-ylcarbamate (1.00 g, 2.69 mmol) and triethylamine (0.374 mL, 2.69 mmol) in DMSO (10 mL) was added (4-methoxyphenyl)methanamine (350 μl, 2.69 mmol) and the reaction mixture was heated in a sealed tube at 95° C. for 16 hr. The resulting mixture was partitioned between water and EtOAc and the organic layer was separated and washed with brine and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate in isohexane, 0-50%, gradient elution) to afford [as judged by LCMS] a 1:1 mixture of the desired compound: tert-butyl 4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)naphthalen-1-ylcarbamate together with 2-chloro-N-(4-methoxybenzyl)pyrimidin-4-amine. This material was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:25])[F:26])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Yield: 56.5 %

Procedure:
1-Benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (1.1 g, 2.4 mmol), and potassium hydroxide (0.44 g, 7.8 mmol) in THF (25 mL) and water (25 mL), according to the procedure described in Step 4 of Example 5. Crystallization from methylene chloride/hexane yielded the title compound as a light yellow solid (0.596 g, 54%), mp: 141-142° C. Mass spectrum (+ESI, [M+H]+) M/z 440; 1HNMR (500 MHz, DMSO-d6): δ13.8-14.2 (br s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 7.7 (m, 2H), 7.6 (t, 3H, J=4.4 Hz), 7.25-7.35 (m, 6H), and 5.65 ppm (s, 2H). Elemental Analysis for C24H16F3NO4: Calculated: C, 65.61; H, 3.67; N, 3.19. Found: C, 65.41; H, 3.39; N, 3.09.
Reaction SMILES: C(C1C=C[S:6]C=1)(=O)C.[S:9]1[CH:13]=[CH:12][C:11]([C:14]([CH2:16][C:17]#[N:18])=[O:15])=[CH:10]1.[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:6][C:28]2[CH2:27][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:31][CH2:30][C:29]=2[C:16]=1[C:14]([C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)=[O:15]
Reactant: N#CCC(=O)c1ccsc1
Reactant: CC(=O)c1ccsc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [S]
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1ccsc1)CCN(Cc1ccccc1)C2
Yield: 68 %

Procedure:
The procedure of Example 1 was followed except that 3-acetyl-thiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-3-carbonyl)acetonitrile (Steps A and B). 1-Benzyl-4-piperidone (van der Klein et al., (1999) J. Med. Chem. 42: 3629-3635), 2-(thiophene-3-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 68%; IR (KBr) cm−1: 3350, 3234, 2805, 1578, 1524, 1429, 1257, 1147, 984, 856, 799, 722; 1H NMR (CDCl3):δ2.14 (m, 2H), 2.54 (t, 2H, J=5.6 Hz), 3.43 (s, 2H), 3.65 (s, 2H), 6.61 (bs, 2H), 7.33 (m, 7H), 7.58 (m, 1H); yellow solid, mp: 131-133° C. (petroleum ether).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#N)[CH:20]=1.[OH2:29]>CCCCCC.CCOCC>[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[C:25]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=[O:29]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: O
Reactant: N#Cc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of n-butyl lithium in hexane (1.6M; 100 mL) at -78° C. under argon, was added dropwise a solution of 3-bromobenzotrifluoride (36 g) in dry ether (75 mL) over 15 minutes. After the addition was complete, the solution was stirred at -78° C. for 45 minutes, then a solution of alpha,alpha,alpha-trifluoro-m-toluonitrile (25.7 g) in dry ether was added over 20 minutes. The deep red mixture was allowed to react at -78° C. for 30 minutes, then immediately after the cooling bath was removed 6N hydrochloric acid (100 mL) was added in a rapid stream. The reaction mixture decolorized and a dense precipitate formed as the reaction temperature rose rapidly to 0°-5° C. Water (200 mL) and ether (200 mL) were added, and the reaction was warmed to 35° C. and was stirred at that temperature until the precipitate dissolved (2 hours). After the reaction was cooled, the layers were separated and the aqueous phase was washed with ether (200 mL). The organic extracts were washed in turn with saturated sodium bicarbonate, then were combined, dried (MgSO4) and evaporated. The solid residue was dissolved in hot hexane (200 mL) and the mixture was left at 0°-5° C. overnight. The resulting colorless crystalline material was filtered, washed with hexane and dried to give 43.9 g of 3,3'-bis(trifluoromethyl)benzophenone mp 98.5°-99.5° C.