Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH:2]1([CH2:7]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=O)[CH3:38]>O1CCCC1.O>[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:38]
Reactant: c1ccc([PH](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
A suspension of cyclopentylmethyl triphenylphosphine iodide (725 mg, 1.53 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and then treated with a 1.0M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.14 mL, 2.14 mmol). The resulting red reaction mixture was stirred at 0° C. for 45 minutes and then slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (355 mg, 1.37 mmol) in tetrahydrofuran (5 mL). The reaction mixture was warmed to 25° C. where it was stirred for 20 h. The reaction mixture was then diluted with water (50 mL) and extracted with diethyl ether (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (Flash 12M, Silica, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethyl ester (267 mg, 60%) as a yellow oil consisting of a 2:1 mixture of (E):(Z) isomers. The isomeric mixture was used without further separation and characterization.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl.N1C=CC=CC=1>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:16]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Nc1cccnc1C1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccnc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyridin-3-ylamine (0.141 g, 0.603 mmol, prepared as described in Example 3: Steps A-B from 3-amino-2-bromopyridine) was dissolved in anhydrous dichloromethane (10 mL) under Ar, treated with methanesulfonyl chloride (0.155 mL, 1.48 mmol), a few drops of anhydrous pyridine, and stirred at ambient temperature for 24 h. The reaction was quenched with saturated aqueous NaHCO3, the aqueous layer extracted thrice with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo giving the title compound as a very hygroscopic yellow solid. ESI-MS (m/z): Calcd. For C14H20N2O4S: 312. found: 313 (M+H)
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10](Cl)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C=O)C.[CH3:25][O:26][CH2:27][CH2:28][OH:29]>>[NH2:2][C:3]1[N:11]=[C:10]([O:29][CH2:28][CH2:27][O:26][CH3:25])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: COCCO
Agent: [Na]
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 130 °C
Yield: 71 %

Procedure:
Sodium (66 mg, 2.9 mmol) in 50 ml of 2-methoxyethanol was added 6-amino-9-benzyl-2-chloropurine (150 mg, 0.58 mmol) and DMF (10 ml). The mixture was heated at 130° C. for 6 hour. The reaction mixture was concentrated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (123 mg, yield 71%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:16])=[N:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Se](=O)=[O:18]>O1CCOCC1.O>[CH:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH:16]=[O:18])=[N:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc2ccc(OC(C)C)c(C)c2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(OC(C)C)ccc2ccc(C=O)nc12
Yield: 35.2 %

Procedure:
To 7-isopropoxy-2,8-dimethylquinoline (120 mg, 0.557 mmol) in dioxane/water (5 mL/0.5 mL) at ambient temperature was added selenium dioxide (74.2 mg, 0.669 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-isopropoxy-8-methylquinoline-2-carbaldehyde (45 mg, 35.2% yield) as a tan solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([OH:25])([C:21]([F:22])([F:23])[F:24])[CH2:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[O:11])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CSc1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 45.5 %

Procedure:
0.50 g (3.01 mmol) of 1-(4-(methylthio)phenyl)ethanone, 0.73 g of (3.01 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.46 g of toluene and 0.17 g (0.90 mmol) of tributylamine were fed and the mixture was stirred for 15 hours at 60° C. After leaving the reaction mixture for one night at room temperature, separation operation was performed by adding 30 ml of ethyl acetate and 10 ml of water, and the ethyl acetate phase was washed with diluted aqueous solution of hydrochloric acid. After removing the solvent by distilling under reduced pressure, the residue was purified by silica gel column chromatography to obtain 0.56 g of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-(methylthio)phenyl)butan-1-one (yield 45.2%).
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][NH:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29].O>CN(C=O)C>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCCl)c1=O
Yield: 95 %

Procedure:
3-Benzoyl-5-iodo-1H-pyrimidine-2,4-dione (Prep128, 2.5 g, 7.3 mmol), K2CO3 (1 g, 7.3 mmol) and 1-bromo-4-chloro-butane (1.26 ml, 10.95 mmol) were suspended in dry DMF (10 ml). After stirring the reaction at room temperature overnight, further 1-bromo-4-chloro-butane (840 μl, 7.3 mmol) was added. Water was added and the mixture was extracted with ethyl ether. The organic phase was dried (Na2SO4), filtered and evaporated; the crude was purified by flash chromatography with petroleum ether-ethyl acetate (7-3) to give the title compound as a white solid (3 g, 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([N:11]2[C:15]([CH3:16])=[C:14](I)[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:12]2)=[CH:5][N:4]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CCCCCC.CCOC(C)=O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]([OH:29])[C:14]2[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:12][N:11]([C:6]3[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)[C:15]=2[CH3:16])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.3 using ethyl 1-(2,4-dimethoxypyrimidin-5-yl)-4-iodo-5-methyl-1H-pyrazole-3-carboxylate (Step 55.2) and 4-chlorobenzaldehyde at RT for 30 min. tR: 4.92 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.24 (Hexane/EtOAc 1:1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Product: Cc1cc(Cl)cc2c(-c3ccccc3)c(C(=O)O)c(N3CCCC3)nc12

Procedure:
The title compound was prepared in analogy to example 40 step D from 2,6-dichloro-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 40 step C) and pyrrolidine. Brown foam. MS (ESI): 367.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:11][NH2:12]>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH2:10])=[N:12][NH:11][C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1cc(Br)cnc1Cl
Reactant: NN
Solvent: CCO
Product: Nc1n[nH]c2ncc(Br)cc12

Procedure:
Compound 3 (307 mg, 1.4 mmol) was dissolved in EtOH (10 mL) in a microwave tube, to which 5 equivalent of NH2NH2 was added, and the reaction mixture was put on Microwave irradiation for 10 min at 170° C. Evaporated the solvent to obtain the title compound 4 in quantative yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=1)[C:5](O)=[O:6].CCN(C(C)C)C(C)C.CN([C:27]([O:31][N:32]1N=NC2C=CC=C[C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNOC>C(Cl)Cl>[CH2:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([CH3:1])[N:10]=1)[C:5]([N:32]([O:31][CH3:27])[CH3:33])=[O:6])[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(C)nc(CC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 2-methyl-6-(2-methyl-propyl)-isonicotinic acid (3.80 g, 16.5 mmol) in DCM (50 mL), DIPEA (10.7 g, 82.7 mmol) followed by TBTU (6.37 g, 19.9 mmol) is added. The mixture is stirred at rt for 10 min before N,O-dimethylhydroxylamine (1.94 g, 19.9 mmol) is added. The mixture is stirred at rt for 1 h before it is diluted with DCM, washed with sat. aq. NaHCO3, followed by water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silic gel eluting with heptane:EA 1:1 to give 2-isobutyl-N-methoxy-6,N-dimethyl-isonicotinamide (3.37 g) as a colourless oil; LC-MS: tR=0.61 min; 1H NMR (CDCl3): δ 0.95 (d, J=6.8 Hz, 6H), 2.06-2.18 (m, 1H), 2.60 (s, 3H), 2.69 (d, J=7.3 Hz, 2H), 3.37 (s, 3H), 3.57 (s, 3H), 7.13 (s, 1H), 7.18 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:10][CH2:3][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: C=C(CBr)c1ccccc1
Yield: 51.5 %

Procedure:
Benzene (120 ml), was mixed with 9.00 g (76.2 mmol), of α-methylstyrene, 14.2 g (80.0 mmol), of N-bromosuccinimide, and 300 mg of benzoyl peroxide and the mixture was refluxed for 24 hours. After the solvent was distilled off under reduced pressure, carbon tetrachloride was added and the resulting crystals were filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane 100%), to obtain the target compound. The yield, % yield and NMR spectrum were as follows. Yield: 7.72 g, % yield: 51.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]Br)[CH2:11][CH2:10]1.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([C:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=3)=[CH:28][NH:29]2)=[CH:25][CH:24]=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][N:35]2[CH2:36][CH:37]=[C:32]([C:27]3[C:26]4[C:30](=[CH:31][C:23]([F:22])=[CH:24][CH:25]=4)[NH:29][CH:28]=3)[CH2:33][CH2:34]2)[CH2:11][CH2:10]1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: COc1ccccc1N1CCN(C(=O)CCCCBr)CC1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(=O)CCCCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)CC1
Yield: 69.7 %

Procedure:
Following the same procedure reported in the Step 2 of EXAMPLE 13, the reaction of 1-(2-methoxyphenyl)-4-(5-bromovaleryl)piperazine (9.29 mmol) with 6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (3.54 mmol) and triethylamine (4.63 mmol) gave the alkylation product (1.21 g, 53%). mp: 78-81° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)=[S:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1COCC1.[Hg](OC(C)=O)OC(C)=O>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:21][N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: CC(=O)O[Hg]OC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A solution of tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonothioyl)piperazine-1-carboxylate (0.66 g, 1.27 mmol) and Lawesson's reagent (0.36 g, 0.89 mmol) in THF (15 mL) was heated at 66° C. for 1 h, then cooled down to rt Hg(OAc)2 (0.4 g) was added and the mixture was stirred at rt overnight. The solution was then concentrated and the residue was purified by silica gel column chromatography (1:2 EtOAc/petroleum ether) to give tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (0.15 g, 24%) as a light yellow solid. ESI-MS (EI+, m/z): 501 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:39][CH2:38][C:11]2[N:12]=[C:13]([C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>O.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:17][O:16][C:15]1[C:10]2[CH2:9][NH:8][CH2:39][CH2:38][C:11]=2[N:12]=[C:13]([C:18]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[N:21][N:22]3[S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[N:14]=1
Reactant: [H][H]
Reactant: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CNCC2

Procedure:
A mixture of 6-benzyl-4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.85 g, 3.43 mmol) and Pd(OH)2 on carbon (wet) (10%, 0.722 g, 1.03 mmol) in water (7.5 mL) and acetic acid (0.59 mL) was stirred under 1 atm of hydrogen at room temperature for 2.5 h. The reaction mixture was filtered through Celite® and the solids were washed with EtOAc. The combined filtrates were washed with saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH (10% NH4OH)/DCM) to provide 4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 450.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:19])[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(OCC)C>C1(C)C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH3:19])[C:7](=[O:20])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 100 °C
Yield: 23.7 %

Procedure:
8-Cyclopentyl-6-methyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 3.43 mmol) was added to 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.91 g, 6.86 mmol) in toluene (5 ml). The mixture was heated to 100° C. over 18 hours then treated with diethyl ether to produce a precipitate. This precipitate was collected by filtration then dried in vacuo to provide 4-[6-(8-cyclopentyl-6-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.411 g). MS (APCI) M++1: Calc'd, 506.28. Found 506.2.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[S:12]([CH:15]1[S:19][C:18](=[O:20])[NH:17][C:16]1=[O:21])(=[O:14])=[O:13].S1CC(=O)NC1=O.C([Li])CCC.[Br:34]C1C=CC=C2C=1C=CC=C2S(Cl)(=O)=O.S(=O)(=O)(O)O>O1CCCC1>[Br:34][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][CH:2]=[C:3]2[S:12]([CH:15]1[S:19][C:18](=[O:20])[NH:17][C:16]1=[O:21])(=[O:14])=[O:13]
Reactant: O=C1NC(=O)C(S(=O)(=O)c2c(Br)ccc3ccccc23)S1
Reactant: O=S(=O)(Cl)c1cccc2c(Br)cccc12
Agent: O=C1CSC(=O)N1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(S(=O)(=O)c2cccc3c(Br)cccc23)S1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
5-[(Bromo-1-naphthalenyl)sulfonyl]-2,4-thiazolidinedione. To a stirred solution of 2,4-thiazolidinedione (5.5 g, 47 mmol) in tetrahydrofuran (THF) (275 mL) at -78° C. under nitrogen was added n-butyllithium (62 mL, 99 mmol) portionwise over 15 minutes. The mixture was maintained at -78° C. for 15 minutes and then warmed to 0° C. for 30 minutes to complete the dianion formation. Upon recooling to -78° C., 5-bromo-1-naphthalene-sulfonyl chloride (16 g, 52 mmol) was added as a solid, all at once. After 30 minutes the solution was allowed to warm to 25° C. After 1.5 hours the reaction mixture was treated with 5% aqueous sulfuric acid. The aqueous phase was washed with chloroform (3×), and the combined organic extracts were concentrated to an oil which was taken up in 5% aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts of the acidified aqueous phase were dried (magnesium sulfate) and then concentrated to give an oil, which was purified by chromatography (acid-washed silica gel, 10:1 chloroform/acetonitrile) to give 5-[(5-Bromo-1-naphthalenyl)sulfonyl]-2,4-thiazolidinedione (7.6 g, 42% yield): mp 189°-190° C. (acetonitrile/chloroform): 1H NMR (DMSO-d6, 200 MHz) δ6.60 (s, 1H, CH, exchanges with D2O), 7,7-8.7 (m, 6H, ArH).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:17])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[F:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[F:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([CH3:17])=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:10]=4)[N:7]=3)[CH2:26][CH2:25]2)=[CH:21][CH:20]=1
Reactant: Cc1c(-c2ccccc2)nc2ccc(Cl)nn12
Reactant: Fc1ccc(CN2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)nc2ccc(N3CCN(Cc4ccc(F)cc4)CC3)nn12
Temperature: 180 °C
Yield: 47 %

Procedure:
A solution of 6-chloro-3-methyl-2-phenylimidazo[1,2-b]pyridazine (1.00 g, 4.35 mmol) and 1-(4-fluorobenzyl)piperazine (Sigma-Aldrich, 1.54 g, 4.35 mmol) in acetonitrile (50 mL) containing triethylamine (13.0 mmol) is heated at 180° C. in the microwave for 5 hours. The reaction mixture is concentrated to dryness and then purified via chromatography (hexanes to EtOAc) to afford the title product (0.82 g, 81%) as an off-white solid: Rf 0.30 (EtOAc); LCMS (m/z)=402.4 [M+H]+, tR=1.74 min. (compound same as Example 134)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:24][CH2:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH2:25][F:24])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC(C)(CF)C(=O)Cl
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C(C)(C)CF)C2)cc1

Procedure:
62 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 42 mg (0.3 mmol, 1.5 eq.) of 3-fluoro-2,2-dimethylpropanoyl chloride were reacted according to General Method 2. Yield: 68 mg (83% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:21][C:22]([S:25]([NH2:27])=[O:26])([CH3:24])[CH3:23].CCOC(C)=O>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:13][CH2:12]3)[C:8]2=[N:27][S:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1c2cc(Br)ccc2CC12CCC1(CC2)OCCO1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
6″-Bromodispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-inden]-1″(3″H)-one (Intermediate 71, 320 mg, 0.95 mmol), 2-methylpropane-2-sulfinamide (173 mg, 1.42 mmol) and titanium ethoxide (0.391 mL, 1.90 mmol) were dissolved in 2-Me THF (5 mL) and heated to reflux overnight. The reaction was stopped and was left to cool down to r.t. EtOAc and water were added under stirring. The mixture was left to stand still for 2 h. The organic phase was collected by filtration, dried using a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in heptane to give the title compound (290 mg, 69% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.35 (s, 9H) 1.48-1.54 (m, 1H) 1.61 (dd, 1H) 1.67-1.77 (m, 2H) 1.81-1.90 (m, 2H) 2.10 (br. s., 2H) 2.95-3.05 (m, 2H) 3.95-4.02 (m, 4H) 7.25 (s, 1H) 7.60 (dd, 1H) 8.62 (br. s., 1H); MS (ES+) m/z 440.0 [M+H]+.