Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH2:37][O:38]C4CCCCO4)[N:22]=3)[CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>[OH-].[Na+]>[OH:38][CH2:37][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(COC4CCCCO4)n3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(CO)n3)n2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
To the above described N-tert-butyl-3-[6′-(tetrahydro-pyran-2-yloxymethyl)-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (0.550 g, 0.88 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 18 h. The mixture was poured into 3 N NaOH-solution (100 ml) and stirred at 23° C. for 15 min, then partitioned between EtOAc and water, the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as an off-white solid (0.100 g, 23%). MS (ISP) 486.0 [(M+H)+]; mp 213° C. (dec.).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CN(C)C=O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19]
Reactant: COc1cccc(CCl)c1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cccc(CN2c3nc(N4CCOCC4)cc(=O)n3CC[C@H]2C(F)(F)F)c1
Yield: 79.6 %

Procedure:
The product is prepared according to the procedure described in Example 22, but using 100 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 57 mg of 1-(chloro-methyl)-3-methoxybenzene and 214 mg of caesium carbonate in 2 ml of dimethylformamide. After treatment, the residue is stirred into acetonitrile. The solid is spin-filter-dried, rinsed with diethyl ether and then dried under a vacuum bell jar. 111 mg of (8S)-9-(3-methoxybenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3C=C(C4C=CC(C5C=CN=CC=5)=CC=4F)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[O:49][N:48]=[C:47]([CH3:50])[N:46]=2)=[CH:41][C:40]=1[O:51][CH3:52])#[CH:38]>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:38]=[C:37]([C:39]4[CH:44]=[CH:43][C:42]([C:45]5[O:49][N:48]=[C:47]([CH3:50])[N:46]=5)=[CH:41][C:40]=4[O:51][CH3:52])[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(-c2nc(C)no2)cc1OC
Reactant: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Product: COc1cc(-c2nc(C)no2)ccc1-c1cn(C2CCc3c(F)cccc3N(CC(F)(F)F)C2=O)nn1

Procedure:
The title compound was prepared by the same route as 6-fluoro-3-{-4-[2-fluoro-4-(pyridin-4-yl)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one using 5-(4-ethynyl-3-methoxy-phenyl)-3-methyl-1,2,4-oxadiazole as the alkyne.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][CH2:10][C@@H:11]([NH:13]C(=O)OC(C)(C)C)[CH3:12])=[CH:5][C:4]=1[NH:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[N:23]=1)#[N:2].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>C(Cl)Cl>[OH:34][C:32]([C:31]([F:36])([F:35])[F:30])=[O:33].[NH2:13][C@@H:11]([CH3:12])[CH2:10][NH:9][C:6]1[CH:5]=[C:4]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[N:23]=2)[C:3]([C:1]#[N:2])=[N:8][CH:7]=1
Reactant: Cc1cc(C)nc(Nc2cc(NC[C@H](C)NC(=O)OC(C)(C)C)cnc2C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(Nc2cc(NC[C@H](C)N)cnc2C#N)c1
Reaction time: 1 h

Procedure:
To a flask containing tert-butyl [(2S)-1-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)propan-2-yl]carbamate (160 mg, 0.404 mmol) were added DCM (3 mL) and trifluoroacetic acid (0.3 mL). After 1 hour, the reaction mixture was concentrated under reduced pressure to afford 5-{[(2S)-2-aminopropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile TFA salt. The material was used without further purification. MS ESI calc'd. for C16H21N6 [M+H]+ 297. found 297.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[C:14]([NH:16][C:17]2([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[CH2:19][CH2:18]2)=[O:15])=[CH:5][CH:4]=1.[Li+:34].[OH-]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[C:14]([NH:16][C:17]2([C:20]3[CH:21]=[CH:22][C:23]([C:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)[CH2:18][CH2:19]2)=[O:15])=[CH:5][CH:4]=1.[Li+:34]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C([O-])c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (E4) (50 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from (R)-methyl 4-(1-(1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D119) (74 mg). (LiOH: 3 eq; Reaction time: 3 hrs; RT)
Reaction SMILES: [OH:1][C:2]1[C:19]2[CH2:18][S:17][CH2:16][C@@H:15]([C:20]([NH2:22])=O)[NH:14][C:13](=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7](=[O:24])[C:6]=2[C:5]([CH3:25])=[C:4]([O:26][CH3:27])[CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C>O1CCOCC1>[C:20]([C@H:15]1[NH:14][C:13](=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7](=[O:24])[C:6]2[C:5]([CH3:25])=[C:4]([O:26][CH3:27])[CH:3]=[C:2]([OH:1])[C:19]=2[CH2:18][S:17][CH2:16]1)#[N:22]
Reactant: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=O)N[C@H](C(N)=O)CSC2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=O)N[C@H](C#N)CSC2
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
To a solution of 60 mg of the product of Example 68 in 1.2 ml of dioxane were added at 0° C. 36 mg of pyridine and 95 mg of trifluoroacetic acid anhydride. The mixture was allowed to warm to 20° C. within 5 min and stirring was continued for 15 min at 20° C. Ethyl acetate was added and the mixture Was washed successively with 1N hydrochloric acid, 5% sodium carbonate solution and brine. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The solid residue was purified by chromatography on silica gel using hexane/ethyl acetate (1:2, v/v) as eluent, to yield 21 mg of (R)-4-cyano-16-hydroxy-14-methoxy-13-methyl-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione as a white solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30]C(OC)=O)=[CH:25][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][N:8]=1.[ClH:35]>CO.O>[ClH:35].[F:3][C:4]1[CH:28]=[C:27]([CH3:29])[C:26]([OH:30])=[CH:25][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COCC(=O)Nc1cc2ncnc(Nc3cc(OC(=O)OC)c(C)cc3F)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCC(=O)Nc1cc2ncnc(Nc3cc(O)c(C)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
2M Aqueous sodium hydroxide solution (620 μl) was added dropwise to a suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-methoxyacetamidoquinazoline (275 mg, 0.62 mmol) in methanol (8 ml) at 5° C. and the mixture then stirred for 90 minutes at ambient temperature. The reaction mixture was diluted with water and adjusted to pH7 with 2M hydrochloric acid. The precipitated solid was collected by filtration, resuspended in ethanol and a 5M solution of hydrogen chloride in isopropanol (0.3 ml) added. The volatiles were removed from the resulting solution by evaporation and the solid washed with ether collected by filtration and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-methoxyacetamidoquinazoline hydrochloride (216 mg, 82%).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][S:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:12][C:11]1[C:2]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[CH:26][CH:27]=2)(=[O:15])=[O:16])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CN(C)C(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN(C)C(=O)c1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Temperature: 135 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
2,3-Dichloroquinoxaline (3.5 g; 17.6 mmol; 1 eq), 4-(aminosulfonyl)-N,N-dimethylbenzamide (4 g; 17.6 mmol; 1 eq) and anhydrous K2CO3 (2.4 g; 17.6 mmol; 1 eq) are taken up in DMA (35 mL) and the resulting suspension is heated at 135° C. for 1 h. After evaporation of the DMA under reduced pressure, the reaction is stopped by addition of water (20 mL) then the suspension is acidified with a 25% aqueous solution of citric acid (70 mL). After overnight standing at 4° C., the yellow precipitate is filtered off, washed several times with water until pH=6 and dried under vacuum at 40° C. overnight affording 5.73 g of a yellow solid. It is taken up in EtOH (25 mL) and the suspension is heated for a few minutes. The precipitate is filtered off and washed twice with EtOH (10 mL) then dried under vacuum at 40° C. overnight to afford 3.96 g (57.6%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 8.27-8.24 (d, J=8.3 Hz, 2H), 7.91 (t, J=7.2 Hz, 2H), 7.79-7.74 (m, 2H), 7.73-7.66 (m, 3H), 3.02 (s, 3H), 2.88 (s, 3H). HPLC (max plot) 95%; Rt 3.18 min. LC/MS: (ES+): 391.3, (ES−): 389.2.
Reaction SMILES: O[C:2]1([C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOCC>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][CH2:4][CH:3]=[C:2]2[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:8]=1
Reactant: COC(=O)C1(O)CCCc2ccc(OC)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C1=CCCc2ccc(OC)cc21

Procedure:
A solution of 1-hydroxy-7-methoxytetralin-1-yl-carboxylic acid, methyl ester (0.5 g; 2.1 mmol; see Example 1(i) above) in toluene (5 mL) was added to a refluxing solution of p-TsOH (0.6 g; 3.2 mmol) in toluene (10 mL), and the resultant mixture was refluxed for 45 minutes. After cooling, the reaction mixture was diluted with ether, washed with water and NaHCO3/aq, dried with Na2SO4 and concentrated. Yield 392 mg (85%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:9]([CH2:11][C:12]2[CH:13]=[C:14]([C@H:24]3[C@H:29]([OH:30])[C@@H:28]([OH:31])[C@H:27]([OH:32])[C@@H:26]([CH2:33][OH:34])[O:25]3)[C:15]3[C:20]([C:21]=2[O:22]C)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][N:7]=1.B(Br)(Br)Br>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:9]([CH2:11][C:12]2[CH:13]=[C:14]([C@H:24]3[C@H:29]([OH:30])[C@@H:28]([OH:31])[C@H:27]([OH:32])[C@@H:26]([CH2:33][OH:34])[O:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][N:7]=1
Reactant: COc1c(Cc2nnc(-c3ccco3)s2)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](c2cc(Cc3nnc(-c4ccco4)s3)c(O)c3ccccc23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 76.5 %

Procedure:
To a solution (2S,3R,4R,5S,6R)-2-(3-((5-(Furan-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-4-methoxynaphthalen-1-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol (compound 71b, 50 mg, 0.10 mmol) in CH2Cl2 (5 mL) at 0° C. was added boron tribromide (1.0 M in CH2Cl2, 0.52 mL, 0.52 mmol). The resulting mixture was stirred with gradual warming to ambient temperature over 2 h and re-cooled to 0° C. The mixture was quenched with MeOH and concentrated in vacuo. The resulting crude residue was purified by reverse phase preparative HPLC to yield the title compound (36 mg, 74%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])#[N:17]>>[C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=1)/[C:16]#[N:17])([O:21][CH3:22])=[O:20]
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Reactant: COC(=O)CC#N
Product: COC(=O)/C(C#N)=C/C=C/c1cc(OC)c(O)c(OC)c1

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.15 g, 0.72 mmol) to methyl cyanoacetate (0.064 ml, 0.72 mmol). After refluxing for 1 h and recrystallization from ethanol an orange solid was obtained (0.2 g, 90%). The product gave the following analytical data:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH2:13][F:14])([CH3:12])[CH2:8][C@H:7]2[NH2:15].[Li]CCCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C@@:9]([CH2:13][F:14])([CH3:12])[CH2:8][C@H:7]2[NH2:15]
Reactant: CC1(CF)C[C@@H](N)c2cccc(F)c2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@]1(CF)C[C@@H](N)c2cccc(F)c2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
A solution of Example 128A (1.99 g, 9.34 mmol) in THF (100 mL) was cooled to 0° C. and n-BuLi (3.74 mL of a 2.5M solution in hexanes, 9.34 mmol) was added while maintaining the internal temperature <0° C. The reaction was warmed to ambient temperature and n-BuLi was added twice more (2 mL for each addition). After 30 minutes, the reaction was quenched by addition of water (25 mL) and extracted with MTBE (50 mL). The organic portion was washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatorgraphy (gradient elution: 0-10% MeOH/EtOAc) to give the title compound (490 mg, 2.30 mmol, 25% yield). MS (LCMS) m/z 197 (M-NH2)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:6].C([C:29]1[C:30]([N:36]=[CH:37][N:38]([CH3:40])C)=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([S:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:2]([NH:1][C:40]3[C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[N:31][C:30]=4[N:36]=[CH:37][N:38]=3)[CH:3]=2)=[CH:10][CH:11]=1
Reactant: Nc1cc(C(=O)NCc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)NCc4ccc(Br)cc4)ccc3Sc3ccc(O)cc3)ncnc2n1
Yield: 40 %

Procedure:
The product of Example 33A was reacted with the product of Example 9B using the procedure of Example 22C substituting the product of Example 33A for the product of Example 22B and substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (40 mg, 40%). 1H NMR (500 MHz, DMSO-D6) δ ppm: 2.67 (s, 3 H) 4.41 (d, J=6.22 Hz, 2 H) 6.83 (d, J=8.82 Hz, 2 H) 6.86-6.95 (m, 1 H) 7.25 (d, J=8.30 Hz, 2 H) 7.28 (d, J=8.82 Hz, 2 H) 7.50 (d, J=8.30 Hz, 2 H) 7.52-7.59 (m, 1 H) 7.65-7.80 (m, 1 H) 7.81-7.98 (m, 1 H) 8.49-8.63 (m, 1 H) 8.69-8.84 (m, 1 H) 8.93-9.01 (m, 1 H) 9.83-9.97 (m, 1 H) 10.11 (s, 1 H); MS (ESI+) m/z 572/574 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:18])[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:29])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:29])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:18])[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2cc(C)c(=O)n(C3CCCC3)c2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reaction time: 16 h
Yield: 84.8 %

Procedure:
8-Cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.56 g, 9.30 mmol) was dissolved in dichloromethane (17 mL) and methanol (17 mL) to which 2-benzenesulfonyl-3-phenyl-oxaziridine was added and the reaction mixture was stirred for 16 hours. The solvent was removed and diethyl ether added. The precipitated solid was collected by filtration to give 8-cyclopentyl-2-methanesulfinyl-6-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (2.30 g, 84.8%). 1H NMR δ (400 MHz, CDCl3) 8.85 (s, 1H), 7.54 (s, 1H), 5.99, (m, 1H), 2.95 (s, 3H), 2.27 (d, J=1.2 Hz, 3H), 2.24 (m, 2H), 2.13 (m, 2H), 1.94 (m, 2H), 1.70 (m, 2H).
Reaction SMILES: [OH-].[Na+].[O:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:10]([OH:11])=[C:7]([O:8][CH3:9])[CH:6]=1.Cl[CH2:15][C:16]([OH:18])=[O:17].Cl>O>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([CH:4]=[O:3])[CH:13]=[CH:12][C:10]=1[O:11][CH2:15][C:16]([OH:18])=[O:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C=O)ccc1OCC(=O)O
Temperature: 25 °C
Yield: 57 %

Procedure:
A solution of 80 g sodium hydroxide in 200 ml water was added to a mixture of 152 g of vanillin, 95 g chloroacetic acid, and 800 ml water with stirring. The mixture was heated to reflux 65 hours, cooled to room temperature, acidified with 70 ml conc. HCl, and the product collected by filtration. The solid was washed with 2 l of distilled water and dried to give 120 g, 57% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:17]([OH:22])[OH:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccccc1CCOC1CCCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccccc1CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a solution of 2-[2-(2-bromophenyl)ethoxy]tetrahydropyran (3.58 g, 12.5 mmol) and triisopropyl borate (3.70 ml, 16.1 mmol) in tetrahydrofuran (10.0 ml) was added a solution (10.0 ml) of 1.6M n-butyllithium in hexane at −78° C., and the mixture was stirred for 2 hr while gradually raising the temperature to 0° C. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give 2-[2-(tetrahydropyran-2-yloxy)ethyl]phenylboronic acid (1.77 g, yield 56.6%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]1.[H-].[Na+].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1COCC1.O>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:1]2[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=Cc1cc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc(C=O)n2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 1H-pyrazole-3-carbaldehyde (3.00 g, 31.22 mmol) in THF was added 60% NaH (1.64 g, 41.00 mmol) in mineral oil. After 20 minutes, p-toluenesulfonyl chloride (7.82 g, 41.00 mmol) was added. After 2 hours, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 10-50% EtOAc in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford (1-(toluene-4-sulfonyl)-1H-pyrazole-3-carbaldehyde) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=1>C(O)C.O.[OH-].[Na+]>[CH2:13]([CH:12]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[N:7]=1)[C:3]([OH:17])=[O:2])[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)c1cc(C(=O)OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(CC)c1cc(C(=O)O)cc(OC)n1
Temperature: 70 °C
Yield: 85.3 %

Procedure:
A solution of 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid methyl ester (50 g, 0.211 mol) in ethanol (250 mL), water (50 mL) and 32% aq. NaOH (50 mL) is stirred at 80° C. for 1 h. The mixture is concentrated and the residue is dissolved in water (200 mL) and extracted with TBME. The org. phase is separated and washed once with water (200 mL). The TBME phase is discarded. The combined aq. phases are acidified by adding 25% aq. HCl and then extracted with EA (400+200 mL). The combined org. extracts are concentrated. Water (550 mL) is added to the remaining residue. The mixture is heated to 70° C., cooled to rt and the precipitate that forms is collected and dried to give the title compound (40.2 g) as a white solid; LC-MS: tR=0.95 min, [M+1]+=224.04; 1H NMR (D6-DMSO): δ 0.73 (t, J=7.3 Hz, 6H), 1.59-1.72 (m, 4H), 2.52-2.58 (m, 1H), 3.88 (s, 3H), 7.00 (d, J=1.0 Hz, 1H), 7.20 (d, J=1.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH3:16].CO>[Ni]>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[O:11][C:10]([CH2:12][NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)o1
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
A suspension of 5-(4-fluoro-phenoxy)-furan-2-carbaldehyde described in Preparation Example 168 (4.3 g, 20.9 mmol), Raney nickel (1.5 g) and 7N ammonia-methanol solution (40 mL) was stirred at room temperature for 15 hours under hydrogen atmosphere (1 atm). The reaction solution was filtered through Celite pad to remove the catalyst, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, filtered by NH silica gel lined over a glass filter, and then, this filtrate was concentrated to obtain the title compound (3.5 g, 16.9 mmol, 81%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2.[H-].[Na+].Br[CH:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH3:20][CH:19]([N:8]1[C:9]2[C:5]3[C:4](=[CH:15][CH:14]=[CH:13][C:6]=3[C:7]1=[O:12])[C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)[CH3:21]
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc2c3c(cccc13)C(=O)N2C(C)C

Procedure:
A mixture of 2.0 g of 6-(methylthio)-benz[cd]indol-2(1H)-one (Example 2), 0.48 g of 60% sodium hydride and 2.33 ml of 2-bromopropane in 100 ml of N,N-dimethylformamide is reacted for 23 hours using the conditions of Example 4 to yield 1.15 g of the desired product as a bright yellow solid, m.p. 70°-71° C.