Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:19]3[CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[C:10]([C:20]#[N:21])=[C:9]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C[O:32]CC1>>[O:32]=[C:18]1[C:19]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[C:10]([C:20]#[N:21])[C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: N#Cc1c(N2CCCC2)cc(-c2ccccc2)c2c1-c1ccccc1C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCC2)cc(-c2ccccc2)c2c1-c1ccccc1C2=O
Temperature: 2.5 °C

Procedure:
A solution of 1-phenyl-3-(pyrrolidin-1-yl)-9H-fluorene-4-carbonitrile (336 mg) in THF was added sodium hydride (45′ mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; mp 202-204° C.; ESIMS 351 (M++1); IR (KBr) 2206 (CN), 1695 cm−1 (CO); 1H NMR (300 Hz, CDCl3) δ 2.05-2.07 (m, 4H, 2CH2), 3.77-3.81 (m, 4H, 2CH2), 6.35 (s, 1H, ArH), 7.31-7.60 (m, 8H, ArH), 8.39 (d, J=7.6 Hz, 1H, ArH).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH2:6][NH2:7].[CH:15](OCC)=O.O.Cl>C(O)C.CO>[ClH:1].[OH:8][C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][NH:3][CH:15]=[N:7][CH2:6]1
Reactant: NCC(O)(CN)c1ccccc1
Reactant: CCOC=O
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: OC1(c2ccccc2)CN=CNC1
Temperature: 100 °C
Yield: 84 %

Procedure:
A mixture consisting of 5.56 g (0.0335 mol) of 1,3-diamino-2-phenylpropan-2-ol dihydrochloride (m.p. (inst.)=242° C.) and 2.479 g (0.0335 mol; 2.7 ml) of ethyl formate is heated at 100° C. for 3 h. It is then heated at 100° C. under reduced pressure (vacuum obtained by means of a water-jet pump) for 1 h. The reaction medium is cooled, taken up with CH3OH, acidified with ethanol containing HCl and evaporated to dryness, and the evaporation residue is triturated with ether, acetone and chloroform. The precipitate formed is collected by filtration and then recrystallized from an ethanol/diethyl ether mixture (1:1 v/v) to give 6 g (yield: 84%) of CRL 41 382. M.p. (inst.)=206° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]=2)[CH2:22][NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:27]=3)[CH2:22][NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NCc2ccc(-c3ccccc3)cc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2ccc(-c3ccccc3)cc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-6-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared. The product was purified by LC 2000 chromatography, eluting with ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C=CC(=O)O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)/C=C\c1ccccc1CBr

Procedure:
A mixture of 2 g (12.34 mmol) of (E) 2-methyl cinnamic acid, 2.19 g (12.34 mmol) of N-bromosuccinimide (NBS) and a catalytic amount of benzoyl peroxide in 6 ml of CCl4 are heated under reflux for hours. The residue is filtered and washed with ether. The organic phase is successively washed with a 1N HCl aqueous solution then with water. It is dried on MgSO4, filtered and evaporated to dryness.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N-:15]=[N+:16]=[N-:17].[Na+].[I-].[Na+]>CS(C)=O>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:15]=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccccc1-c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.6 %

Procedure:
To a solution of 2-(bromomethyl)biphenyl (1.5 g, 6 mmol) in DMSO (15 mL) was added sodium azide (0.59 g, 9 mmol) and a catalytic amount of sodium iodide. The mixture was stirred at room temperature for 2 days. After concentration under reduced pressure, the residue was diluted with ethyl acetate. The organic layer was washed with brine (2×60 mL), dried on sodium sulphate and after filtration was evaporated to dryness to give the title compound as an oil (1.1 g, 87%). 1H NMR (300 MHz, CDCl3, ppm) δ: 7.56-7.38 (m, 9H), 4.37 (s, 2H).
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])C.[CH:11]1[CH:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20](C=O)[C:14]2=[CH:13][CH:12]=1.[H-].[Na+]>C(O)C>[C:16]1([CH:6]([CH:5]=[CH2:4])[C:7]([OH:9])=[O:8])[C:15]2[C:14](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)CCC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: C=CC(C(=O)O)c1cccc2ccccc12

Procedure:
To a solution of 8.71 g of succinic acid ethyl ester and 7.81 g of 1-naphthylaldehyde in 50 ml of absolute ethanol was added 3.02 g of a 50% sodium hydride (suspension in oil) under ice-cooling, and then the mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether to remove neutral materials. The aqueous layer was acidified by adding concentrated hydrochloric acid and extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The ethereal solution was concentrated under reduced pressure to obtain 11.8 g of 3-ethoxycarbonyl-4-(1-naphthyl-3-butenoic acid as a yellow oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1.Cl[CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([O:17][CH2:16][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1)=[O:23]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCn1cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Sodium hydride (218 mg) was added to a solution of 1H-indole-3-carboxylic acid (400 mg) in N,N-dimethylformamide (4 ml) with ice cooling, and the mixture was stirred for 30 minutes. Chloromethyl2,2-dimethylpropionate (373 mg) was added thereto, and the mixture was warmed to room temperature and stirred for 2 hours. Water was added thereto, and the aqueous phase was washed with ether. The aqueous phase was acidified by 2 N hydrochloric acid and extracted with ether. The organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give the title compound (540 mg, Y.:79%) as orange crystals.
Reaction SMILES: [OH-].[Na+].O.[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:11]([NH2:25])[O:10]1.S(OC)(O[CH3:30])(=O)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)=[C:11]([NH:25][CH3:30])[O:10]1
Reactant: COS(=O)(=O)OC
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2cccs2)O1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2cccs2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In this example about 0.36 g of solid sodium hydroxide was dissolved in a small amount of water and then added to 100 ml of methylene chloride containing 1.4 g of 2-thien-2-yl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran. 0.20 g of benzyltriethylammonium chloride was added and then a mixture containing 0.84 ml of dimethyl sulfate in about 5.0 ml of methylene chloride was slowly added at room temperature. The mixture was stirred at room temperature for about one hour and then washed twice with water, twice with 1N. aqueous hydrochloric acid, twice with sodium bicarbonate, dried over magnesium sulfate and then concentrated by evaporation under vacuum. The residue was then triturated in a mixture of ethyl ether and petroleum ether affording 1.4 g of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C@H:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]2.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:29][CH3:30])[CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C@H:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]3)=[C:24]([O:29][CH3:30])[CH:23]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(Br)cc3OC)ccc21
Temperature: 80 °C

Procedure:
To a solution of ethyl [(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (1.4 g, 4.10 mmol) (Example 45) in DMF (130 mL, containing 1 vol % water) was added 4-bromo-2-methoxyphenol (832.9 mg, 4.10 mmol) followed by Cs2CO3 (2.66 g, 8.18 mmol). The reaction mixture was heated for 12 h at 80° C. Upon cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (gradient 1:4 to 1:1 (v/v) EtOAc/hexane) to give the product as a colorless oil. 1H NMR (400 MHz, acetone-d6) δ 7.11-7.07 (m, 2H), 7.03-7.01 (m, 1H), 6.94-6.92 (m, 1H), 6.82-6.81 (m, 1H), 6.75-6.72 (m, 1H), 4.20-4.11 (m, 6H), 3.84 (s, 3H), 3.48-3.44 (m, 1H), 2.89-2.69 (m, 3H), 2.42-2.30 (m, 2H), 2.07 (q, 2H), 1.75-1.70 (m, 1H), 1.25 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH2:37])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47].Cl>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:37][C:46](=[O:48])[CH3:47])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:27])=[O:28])=[C:11]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a Solution of (S)-2-Amino-3-{3-Benzyloxy-4-[1,1,4-Trioxo-5-(2-Trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid tert-butyl ester (150 mg, 0.27 mmol) and triethylamine (0.57 mL, 0.41 mmol) in methylene chloride (10 mL) at 0° C. is added acetyl chloride (0.21 mL, 0.3 mmol) dropwise then the mixture is stirred at RT for 2 h. Water and 1N HCl is added until pH 4 and the mixture is extracted with methylene chloride. The organic phase is washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])=[O:31])=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COC(=O)Nc1ccc(Cl)cc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:33][S:34][CH3:35])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl>O1CCOCC1>[NH2:1][C@@H:2]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:33][S:34][CH3:35])=[O:29])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:10])=[O:11]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)C(N)=O
Yield: 45 %

Procedure:
Condensation of BocDArg(Tos)OH (2.14 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 1.49 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocDArg(Tos)-Leu-MetNH2 in 54% yield. De-t-butoxycarbonylation of BocDArg(Tos)-Leu-MetNH2 (1.7 g.) using hydrogen chloride in dioxane gave HDArg(Tos)-Leu-MetNH2 in 45% yield.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH:10]1[CH2:12][CH2:11]1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:10]1([N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:12][CH2:11]1
Reactant: Ic1cn[nH]c1
Reactant: BrC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Ic1cnn(C2CC2)c1
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-Iodo-1H-pyrazole (2.0 g, 10.3 mmol) in DMF (100 mL) at room temperature was added sodium hydride (0.45 g of a 60% wt/wt dispersion in mineral oil, 11.3 mmol). After 15 minutes, bromocyclopropane (2.5 mL, 30.9 mmol), and tetra-n-butyl ammonium iodide (0.020 g) were added, and the reaction mixture was warmed to 140° C. for overnight. The mixture was subjected to standard aqueous workup, and the crude residue was purified on silica gel (0-20% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH:20]1[C:25](O)=[O:26].CS(C)=O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:9][C:25](=[O:26])[CH:20]3[CH2:21][O:22][CH2:23][CH2:24][N:19]3[C:6]=2[N:7]=1
Reactant: O=C(O)C1COCCN1
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A round-bottomed flask equipped with a magnetic stirrer was added 2,4-dichloropyrimidin-5-amine (1.89 g, 11.52 mmol), DIPEA (8.05 ml, 46.1 mmol), morpholine-3-carboxylic acid (1.66 g, 12.68 mmol), and DMSO (5 ml). The reaction was stirred at 100° C. overnight. The reaction mixture was poured into water and extracted with EtOAc 3 times. The pH of the aqueous layer was adjusted (about 5) with 10% citric acid and extracted again with EtOAc. The combined organic layer dried over MgSO4, filtered, and concentrated in vacuo to furnish a tan solid. The solid was triturated in diethyl ether containing a small amount of EtOH, filtered, and dried to give 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one: 1.95 g (70.3%). MS [M+H] found 241.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[CH:22]([CH3:29])[CH2:23][C:24]([O:26]CC)=[O:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:30])[CH:22]([CH3:29])[CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CC(=O)O)C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 65 °C
Yield: 78.5 %

Procedure:
A mixture of 4-[4-(3-ethoxycarbonyl-2-methyl-propionyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (Example 189 step 2) (5.7 g, 14 mmol) and 1N NaOH (18 mL) in methanol was heated at 65° C. for 1 h. Methanol was evaporated at reduced pressure and diluted with water then cooled to 0° C. The aqueous layer was neutralized carefully with citric acid and extracted twice with methylene chloride to obtain a crude 4-[4-(3-carboxy-2-methyl-propionyl)phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (4.3 g, 81%), MS m/z 390 (M-1)
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]1([CH2:14][CH2:15][SH:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]1[N:26]=[C:25](Cl)[N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cl-].[Na+].O>[NH2:17][C:18]1[N:26]=[C:25]([S:16][CH2:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: SCCc1ccccc1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(SCCc2ccccc2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 36.2 %

Procedure:
Sodium hydride (300 mg, 7.5 mmol 60% in mineral oil) were added DMF (10 ml), 2-phenylethanethiol (1 ml, 7 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred at 100° C. for 10 hours. After addition of saturated brine the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (51 mg, yield 37%).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:17]([OH:18])=[C:16]([C:19]([CH3:21])=[O:20])[CH2:15][S:14]2)=[CH:9][CH:8]=1.S(Cl)(Cl)(=O)=O>O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][CH:15]=[C:16]([C:19]([CH3:21])=[O:20])[C:17]=2[OH:18])=[CH:11][CH:12]=1
Reactant: COc1ccc(C2SCC(C(C)=O)=C2O)cc1
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2scc(C(C)=O)c2O)cc1
Temperature: -12 °C
Reaction time: 0.7 h
Yield: 105.4 %

Procedure:
A chloroform (67 mL) solution of 2-(4-methoxyphenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (6.67 g, 18.45 mmol, purity: 80%) was cooled to −16° C., and to this solution, a chloroform (13 mL) solution of sulfuryl chloride (1.78 mL, 1.2 equivalent amounts) was dropwise added over a period of 20 minutes, followed by stirring at −12° C. for 42 minutes. The temperature of the solution was raised to −3° C., and water (13 mL) was dropwise added over a period of 5 minutes, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a saturated sodium hydrogencarbonate aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was isolated and purified by silica gel column chromatography (eluent: hexane/ethyl acetate/chloroform=7.5/2.5/1 (v/v/v)) to give the desired product as a yellow solid (4.83 g, yield: 73%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:22][C:23]#[N:24]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:22][C:23]#[N:24])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Yield: 999.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol), NaHCO3 (2.5 g, 3.0 mmol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH3CN (150 mol) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous solution was extracted with EtOAc. The EtOAc extract was washed with H2O, washed with brine, dried with MgSO4 and concentrated to yield 7.0 g of a tan solid. A 1.3 g sample was recrystallized from EtOAc to yield 0.65 g of a beige solid, m.p. 154°-156° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[O:13][N:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]([C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH:16]1([C:14]2[O:13][N:12]=[C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:32]5[C:28]([C:21]6[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=6[F:19])=[N:29][N:30]([C:42]([C:55]6[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=6)([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)[C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)[CH:31]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[N:15]=2)[CH2:18][CH2:17]1
Reactant: Brc1ccc2ncc(-c3noc(C4CC4)n3)n2c1
Reactant: COc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4noc(C5CC5)n4)n3c2)c(F)c1
Yield: 73.4 %

Procedure:
82 mg 6-bromo-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-imidazo[1,2-a]pyridine (compound in Production Example 255), 227 mg 3-(2-fluoro-4-methoxyphenyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-trityl-1H-pyrazole (compound in Production Example 185), 86 mg tripotassium phosphate hydrate and 31 mg tetrakis(triphenylphosphine)palladium were stirred at 80° C. for 14 hours in 3 mL N,N-dimethylformamide under nitrogen atmosphere. Water and ethyl acetate were added thereto, then the reaction solution was filtered through Celite, and the organic layer was washed with brine. The solution was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 130 mg of the title compound (colorless oil).