Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](N(CC)CC)[CH3:23].C(Cl)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13]2[N:14]=[C:22]([CH3:23])[O:16][N:15]=2)=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=N)NO)c(I)cc1OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: COc1cc(-c2noc(C)n2)c(I)cc1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of 4-benzyloxy-N-hydroxy-2-iodo-5-methoxy-benzamidine (reference example 3-1) (35 g), triethylamine (31 mL) and tetrahydrofuran (31 mL) was added acetyl chloride (8.2 mL) under ice-bath cooling. The mixture was stirred at the same temperature for 1 hour. Insoluble materials were removed by filtration. To the filtrate was added tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 89 mL). After stirring at the same temperature for 2 hours, water and ethylacetate were added to the mixture. The separated organic layer was washed with 1 mol/L hydrochloric acid, a 1 mol/L aqueous solution of sodium hydroxide, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol to give the title compound (31.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH:13]([CH3:15])[CH3:14])[C:16](=[O:18])[O:17][CH2:19]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
In toluene (250 mL) were suspended benzyloxycarbonyl-L-valine (25.1 g), paraformaldehyde (6.70 g) and p-toluenesulfonic acid monohydrate (0.19 g), and the suspension was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give the title compound (23.7 g) as colorless transparent syrup in an yield of 90%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[CH3:9])=[O:6].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[C:63]1([SH:69])[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C(N(C(C)C)C(C)C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:20][C:19]1[CH:18]=[CH:17][C:4]([C:5]([NH:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH3:9])=[O:6])=[CH:3][C:2]=1[S:69][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: C[C@@H](NC(=O)c1ccc(Cl)c(Br)c1)c1cccc(Cl)c1
Reactant: Sc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)c1ccc(Cl)c(Sc2ccccc2)c1)c1cccc(Cl)c1
Reaction time: 18 h
Yield: 92.3 %

Procedure:
To a mixture of (R)-3-bromo-4-chloro-N-(1-(3-chlorophenyl)ethyl)benzamide 32 (0.634 g, 1.7 mmol), Pd2(dba)3 (0.100 g, 0.11 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.125 g, 0.22 mmol) was added benzenethiol (0.173 mL, 1.7 mmol), dioxane (4.5 mL) and N-ethyl-N-isopropylpropan-2-amine (0.590 mL, 3.4 mmol). The reaction mixture was degassed and heated to reflux. After 18 h, the reaction mixture was diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 5% to 30% EtOAc in hexanes) gave (R)-4-chloro-N-(1-(3-chlorophenyl)ethyl)-3-(phenylthio)benzamide 33 (0.631 g, 92% yield) as a white solid. Mass spectrum: calculated for C21H17Cl2NOS 401.0. found 402.1 (M++1).
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[O:22].O>CC(N(C)C)=O>[O:22]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:20][N:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: Cc1ccccc1C(=O)CBr
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1C(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Temperature: 0 °C

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.0 g, 1 eq.) was suspended in dimethylacetamide (DMA) (30 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (380 mg, 2.0 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and 2-bromo-1-(o-tolyl)ethanone (1.2 g, 1.2 eq.) was added. The reaction was stirred at 50° C. overnight. The reaction was poured onto 80 mL water and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with water (2×100 mL), brine (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product, 5-(2-oxo-2-(o-tolyl)ethyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.65 g) was used without purification. LCMS: 344 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[Br:18])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:39][C:40](O)([CH3:42])[CH3:41].C1CCN2C(=NCCC2)CC1.Cl>CN(C=O)C>[C:40]([O:13][C:12](=[O:14])[C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]([Br:18])=[C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)([CH3:42])([CH3:41])[CH3:39]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Reactant: CC(C)(C)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of 3,5-bis-benzyloxy-4-bromo-benzoic acid (200b) (153 g, 0.37 mol) in DMF (1 L) was added CDI (90 g, 0.56 mol) in several portions. The solution was stirred at 40° C. for 1 hr. t-BuOH (55 g, 0.74 mol) was added to the mixture and then followed by the drop wise addition of DBU (56.3 g, 0.37 mol). The resulting solution was stirred at 40° C. for 2 days. TLC (EtOAc/petroleum ether=1/10) showed that the reaction was complete. The mixture was cooled to room temperature and poured into ice water (1 L). The mixture was acidified to pH 5 with conc. HCl and stirred for 1 hr. The formed solid was filtered and washed with water, then dried in vacuo to give the title compound (165 g, 86% yield) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 7.57-7.25 (m, 12H), 5.21 (s, 4H), 1.58 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[C:16]([Mg]Cl)#[CH:17].O>O1CCCC1>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]([OH:12])[C:16]#[CH:17])=[CH:13][CH:14]=1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Reactant: C#C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(OCCCN(C)C)cc1

Procedure:
To a solution of 4-(3-dimethylaminopropoxy)benzaldehyde (0.83 g, 4 mmol) (Aldrich) in dry tetrahydrofuran (30 mL) under argon at room temperature was added ethynylmagnesium chloride (5 mmmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich) dropwise. The resulting solution was stirred for 1.5 h at which time 100 mL water was added, and the THF was removed in vacuo. The product was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give clean 3-[4-(3-dimethylaminopropoxy)-phenyl]-3-hydroxy-1-propyne which was used directly, without further purification. (Yield 831 mg, 89%)
Reaction SMILES: [NH2:1][C@H:2]([C:9]([NH:11][C@@H:12]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)=[O:14])=[O:10])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[N:30]([C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1)=[C:31]=[S:32].CCN(C(C)C)C(C)C>C(#N)C>[I:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[C@@H:2]([NH:1][C:31]([NH:30][C:33]2[CH:34]=[CH:35][C:36]([S:39](=[O:41])(=[O:40])[NH2:42])=[CH:37][CH:38]=2)=[S:32])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)CC[C@H](NC(=O)[C@@H](N)CCC(=O)OC)C(=O)NCc1ccc(I)cc1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC[C@H](NC(=O)[C@H](CCC(=O)OC)NC(=S)Nc1ccc(S(N)(=O)=O)cc1)C(=O)NCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (S)-methyl 4-(tert-butoxycarbonylamino)-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate (0.448 g, 0.723 mmol) in DCM (10 mL) and TFA (4.0 mL) was stirred at room temperature overnight. After the solvent was evaporated, the reaction mixture was diluted with DCM, washed with sat. K2CO3 and concentrated in vacuo to afford (S)-methyl 4-amino-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate. A solution of the above product ((S)-methyl 4-amino-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate), 4-isothiocyanatobenzenesulfonamide (0.171 g, 0.80 mmol) in acetonitrile (10 mL) containing DIPEA (0.40 mL) was stirred at room temperature under nitrogen for 48 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography 5% MeOH in DCM as eluent to give (S)-methyl 5-(4-iodobenzylamino)-4-((S)-5-methoxy-5-oxo-2-(3-(4-sulfamoylphenyl)thioureido)pentanamido)-5-oxopentanoate (0.469 g) as a white solid. MS (ESI), 756 (M+Na)+, 377 (M/2+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:34][CH3:35])[N:12]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:34][CH3:35])[N:12]=1
Reactant: COc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
1,1-Dimethylethyl 4-[2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl sulfamoyl]piperazine-1-carboxylate (the product of step i) (0.36 g) and trifluoroacetic acid (1 mL) in dichloromethane (4 mL) were stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene (3×). The residual pale yellow solid was triturated with EtOAc, filtered and dried at 40° C. under high vacuum to give the title compound as a cream solid. Yield: 0.24 g.
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[F:15])/[C:5]([C:7]1[S:11][C:10]([NH:12][CH3:13])=[N:9][C:8]=1[CH3:14])=O.[NH:17]([C:21]1[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)[C:18]([NH2:20])=[NH:19]>O(CCO)C>[F:15][C:4]1[C:5]([C:7]2[S:11][C:10]([NH:12][CH3:13])=[N:9][C:8]=2[CH3:14])=[N:19][C:18]([NH:17][C:21]2[CH:22]=[C:23]([S:27]([NH2:30])(=[O:28])=[O:29])[CH:24]=[CH:25][CH:26]=2)=[N:20][CH:3]=1
Reactant: CNc1nc(C)c(C(=O)/C(F)=C/N(C)C)s1
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Solvent: COCCO
Product: CNc1nc(C)c(-c2nc(Nc3cccc(S(N)(=O)=O)c3)ncc2F)s1
Temperature: 140 °C

Procedure:
A mixture of (Z)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (1 mmol) and 3-guanidinobenzenesulfonamide (2 mmol) in 2.5 mL 2-methoxylethanol was heated at 140° C. for 45 minutes under microwave radiation. The mixture was purified by column chromatography using EtOAc/PE or EtOAc/MeOH to yield the titled compound as yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].Br[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C#Cc1cncc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c([N+](=O)[O-])c2)c1
Yield: 43.3 %

Procedure:
Sequentially add 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.100 g, 0.14 mmol) and copper (I) iodide (53 mg, 0.28 mmol) to a solution of 4-bromo-1-fluoro-2-nitrobenzene (616 mg, 2.8 mmol) in triethyl amine (6 mL) and heat for 2 h at 60° C. Add additional 3-ethynyl-5-methoxypyridine (100 mg, 0.75 mmol) and continue heating for 1 h. Concentrate and purify the residue by silica gel chromatography, eluting with 30:70 to 40:60 ethyl acetate:hexanes, to give the title compound as a pale yellow solid (330 mg, 43%).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:16](=O)[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH3:15])=[C:10]([N+:26]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:29])[CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:15][N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:2]([CH3:1])[CH2:3][C:4](=[O:29])[NH:5][N:6]=3)=[CH:9][C:10]=2[N:26]=[C:16]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)N(C)c2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2nc3cc(C4=NNC(=O)CC4C)ccc3n2C)cc1

Procedure:
A mixture of 6.4 gm of 5-methyl-6-{3-nitro-4-[N-methyl-(4-methoxy-benzoyl)-amino]-phenyl}-4,5-dihydro-2H-pyridazine-3-one and 0.6 gm of 10% palladium charcoal in 100 ml of ethanol was treated for 2.5 hours at room temperature with hydrogen at 5 bar. The catalyst was suction filtered off, and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silicagel (eluting agent: methylene chloride/ethanol 19:1 to 9:1). The corresponding fractions were evaporated and the product was crystallized by trituration with ether.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Br[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:13]2)[C:5]([O:23][CH3:24])=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH3:3])[CH:9]=1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 3-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]azetidine-1-carboxylate (0.36 g, 1.0 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.43 g, 1.5 mmol, from Example 108, Step 1) and DIPEA (0.53 mL, 3.0 mmol) in ethanol (6 mL) was heated at 100° C. overnight. The mixture was concentrated and purified on silica gel column (eluting with 0 to 100% EtOAc in hexanes) to give tert-butyl 3-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]azetidine-1-carboxylate. LCMS calculated for C28H38 ClN6O4 (M+H)+: m/z=557.3. found: 557.3. The Boc intermediate isolated was treated with trifluoroacetic acid (0.8 mL, 10 mmol) in methylene chloride (5 mL) at room temperature for 1 hour. The mixture was stripped to dryness to give the desired product as TFA salt. 4 mg of the salt was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C18H22ClN6O (M+H)+: m/z=373.2. found: 373.1
Reaction SMILES: C([S:4][CH:5]([CH2:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=O)C.O.S(=O)(=O)(O)O>O1CCOCC1>[SH:4][CH:5]([CH2:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)SC(CC(=O)c1ccc(Oc2ccccc2)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C(CC(S)C(=O)O)c1ccc(Oc2ccccc2)cc1
Yield: 38.4 %

Procedure:
3.44 g of 2-acetylthio-3-(4-phenoxybenzoyl)propionic acid were dissolved in 50 ml of dioxane, then 5 ml of distilled water and 2 ml of concentrated sulfuric acid were added, and the mixture was refluxed for 3 hours. The dioxane was removed by evaporation under reduced pressure. Diethyl ether was added to the residue, which was extracted with a saturated aqueous solution of sodium hydrogencarbonate. The extract was washed with diethyl ether, made slightly acidic by addition of dilute hydrochloric acid, and extracted with diethyl ether. The diethyl ether layer was washed with water and dried over magnesium sulfate. The diethyl ether was distilled off and the residue was purified by first by silica gel column chromatography, eluted with a mixture of hexane and dichloromethane, and then by recrystallization from a mixture of hexane and acetone to give 1.16 g of 2-mercapto-3-(4-phenoxybenzoyl)propionic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[CH3:9][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:9][C:4]1([CH2:7][NH2:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: N#CC1CCOCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(CN)CCOCC1
Reaction time: 1.5 h

Procedure:
A mixture of tetrahydropyran-4-carbonitrile (5.00 g) and THF (50 ml) was admixed at 0° C. with lithium hexamethyldisilazide (1 M, 63 ml), and, after 90 minutes, methyl iodide (4.26 ml) was added dropwise with good cooling. After 12 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in THF (200 ml), and lithium aluminum hydride (3.79 g) was added. The mixture was boiled at reflux for 6 hours, Water (3.8 ml) and then sodium hydroxide solution (40%; 3.8 ml) were cautiously added dropwise to the cooled suspension. The precipitate was filtered off and the filtrate was concentrated. This afforded the product with the molecular weight of 129.20 (C7H15NO); MS (ESI): 130 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=1>ClCCl.CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: Cc1cc(N)ccn1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4ccnc(C)c4)c3cc2OC)c1
Yield: 19 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol) with 4-amino-2-methylpyridine (28 mg, 0.26 mmol) and chromatography (silica gel, dichloromethane/methanol: 4/1) gives the desired product in 19% yield (21 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH:22]1[CH2:27][CH3:28]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][CH2:26][CH:21]([NH2:20])[CH:22]([CH2:27][CH3:28])[CH2:23]4)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(F)c(F)cc2c1=O
Reactant: CCC1CNCCC1N
Solvent: CC#N
Product: CCC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCC1N
Yield: 71 %

Procedure:
The condensation of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-naphthyridine-3-carboxylic acid with 4-amino-3-ethylpiperidine was carried out in acetonitrile in a similar manner as described in example 1, gave the titled product. Yield 71%, m.p 218–20° C., C19H23FN4O3, m/z 375 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:5]2.[NH4+:27].[Cl-]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([C:18]([NH2:27])=[O:20])[CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:5]2
Reactant: [NH4+]
Reactant: O=C(O)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1
Agent: [Cl-]
Product: NC(=O)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
4-(5-Chloro-2-phenyl-1H-indol-7-yl)amino-cyclohexane-1-carboxylic acid prepared in Example 102 and NH4Cl were reacted according to the same procedure as Example 92 to give the title compound.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:10](=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13]>>[OH:12][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][C:10]([NH2:13])=[O:11]
Reactant: O=C1CCC(c2ccccc2)O1
Reactant: N
Product: NC(=O)CCC(O)c1ccccc1
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of γ-phenyl-γ-butyrolactone (10.30 g, 63.5 mmol) and an excess of ammonia was stirred under nitrogen and a dry ice trap for 8 hours. The dry ice trap was removed and after evaporation of the ammonia 11.27 g of a tan solid remained. Recrystallization of the solid from ethyl acetate-hexane gave 4-hydroxy4-phenyl-butyramide (8.56 g, 75%) as a white solid, mp 85-87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[CH:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=3)[CH:10]=2)[C:6]([CH3:16])([CH3:15])[C:7]1=[O:14])([CH3:12])[CH3:13]
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)N1C(=O)C(C)(C)c2ccc(N)cc21
Product: CC(C)N1C(=O)C(C)(C)c2ccc(NC(=O)c3cccnc3)cc21

Procedure:
Prepared in analogy to example 26 from 6-amino-1-isopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one and nicotinic acid. The title compound was obtained as white foam.