Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[NH:7][C@H:8]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[OH:53])[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[O:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[C:13]([CH3:33])[N:12]([CH2:34][C:35]2[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:36]=2[F:45])[C:11]1=[O:46])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:61]([O:65][C:66](=[O:69])[CH2:67]Br)([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C.ClCCl>[C:61]([O:65][C:66](=[O:69])[CH2:67][O:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:54])[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3[O:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)[CH2:21][CH2:22]2)=[C:13]([CH3:33])[N:12]([CH2:34][C:35]2[C:40]([C:41]([F:43])([F:44])[F:42])=[CH:39][CH:38]=[CH:37][C:36]=2[F:45])[C:11]1=[O:46])([CH3:64])([CH3:63])[CH3:62]
Reactant: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2O)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2OCC(=O)OC(C)(C)C)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A solution of [(R)-2-{3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-3,6-dihydro-2H-pyrimidin-1-yl}-1-(2-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (100 mg, 0.13 mmol), potassium carbonate (36 mg, 0.26 mmol), and bromo-acetic acid tert-butyl ester (38 μl, 0.26 mmol) were dissolved at 70° C. for 4 hrs in DMF (1 mL) with stirring, and then chilled to room temperature. The solution was diluted in dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic layer thus formed was separated and concentrated, and the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 2/1) and dried in a vacuum to afford 51 mg of the compound as a white oil (yield 44%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([SH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:14]([O:16][CH:17]([O:27][CH2:28][CH3:29])[CH2:18]OS(C(F)(F)F)(=O)=O)[CH3:15].C(N(C(C)C)CC)(C)C.FC(F)(F)S([O-])(=O)=O>ClCCl.CCN(C(C)C)C(C)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13][CH2:18][CH:17]([O:27][CH2:28][CH3:29])[O:16][CH2:14][CH3:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(COS(=O)(=O)C(F)(F)F)OCC
Reactant: CC(=O)N1CCc2cc(S)ccc21
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CSc1ccc2c(c1)CCN2C(C)=O)OCC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76.5 %

Procedure:
A mixture of thiol (D3, 3.38 g, 17.5 mmol), acetal trifluoromethanesulphonate (D4, 5.05 g, 19 mmol) and diisopropylethylamine (3.2 ml, 19 mmol) in dry dichloromethane (80 ml) was stirred for 4.5 h at room temperature. Further small portions of trifluoromethane sulphonate and of DIPEA (2 drops each) were added and stirring was continued for another 1 h before the mixture was washed sequentially with dilute hydrochloric acid, dilute sodium hydroxide, and water. The organic phase was dried and evaporated, and the residue was chromatographed on silica (300 g) eluted with ethyl acetate to give the title compound (4.14 g, 76.6%), as a waxy solid, mp <52° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[CH2:13][O:12][C:11]=2[N:17]=1.I[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.CNCCNC.[F-].[Cs+]>CC#N.[Cu]I>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([N:15]2[C:14](=[O:16])[CH2:13][O:12][C:11]3[N:17]=[C:7]([NH:6][CH2:5][C:4]4[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:3]=4[O:2][CH3:1])[CH:8]=[CH:9][C:10]2=3)=[CH:26][CH:27]=1
Reactant: COc1ccc(CNc2ccc3c(n2)OCC(=O)N3)c(OC)c1
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(CNc2ccc3c(n2)OCC(=O)N3c2ccc(Cl)cc2)c(OC)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
6-(2,4-Dimethoxy-benzylamino)-1H-pyrido[2,3-b][1,4]oxazin-2-one (3.76 g, 11.9 mmol), 4-iodo-chlorobenzene (3.4 g, 14.3 mmol), N,N′-dimethylethylenediamine (1.27 mL, 11.9 mmol), and CsF (4.5 g, 29.7 mmol) were suspended in MeCN (100 mL) and sparged with nitrogen. CuI (238 mg, 1.19 mmol) was then added and the mixture stirred at 80° C. for 16 hours. The mixture was allowed to cool and was then concentrated in vacuo. The residue was partitioned between EtOAc and aqueous potassium hydrogenphosphate solution. The EtOAc layer was then washed with saturated aqueous ammonium chloride solution, brine, dried over MgSO4, filtered and then concentrated in vacuo. The residue was purified using SiO2 chromatography (20-70% EtOAc/Petrol) to give 1-(4-chloro-phenyl)-6-(2,4-dimethoxybenzylamino)-1H-pyrido[2,3-b][1,4]oxazin-2-one (4.42 g) as a pale yellow crystalline solid. MS: [M+H]+=426.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16](O)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:46][CH2:45]1>C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:44]2[CH2:45][CH2:46][CH:47]([CH2:50][N:51]3[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)[CH2:48][CH2:49]2)=[O:17])=[CH:19][CH:20]=1
Reactant: C1CCN(CC2CCNCC2)CC1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC(CN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The following was added to DCM (6 mL): 1-(4-chlorobenzyl)-1H-indole-2-carboxylic acid (110 mg, 0.380 mmol), DIPEA (0.5 mL, 2.95 mmol), EDC (100 mg, 0.506 mmol), HOBT (80 mg, 0.506 mmol), and 1-(piperidin-4-ylmethyl)piperidine (150 mg, 0.843 mmol). The solution was stirred at rt for 15 h, at which time the solution was diluted with a 1:1 solution of ethyl acetate:diethyl ether and washed with water (1×), 10% aq. sodium carbonate (1×), and brine (1×). The organic phase was then dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified via silica gel flash chromatography (40 g silica, 10% EtOAc/hexanes) and triturated with ethyl acetate and hexanes to afford the title compound as a white powder. (Yield: 109 mg, 0.242 mmol, 70%) 1H NMR (400 MHz, CDCl3) δ 7.63, 7.35, 7.23-7.12, 7.03, 6.59, 5.46, 4.59, 4.09, 2.75, 2.34, 2.08, 1.71-1.46, 1.46-1.36
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5](O)=[O:6].C[CH2:13][N:14](C(C)C)[CH:15](C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([N:14]([CH3:15])[CH3:13])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)C)cc(Cl)n1
Reaction time: 0.08 h

Procedure:
To a solution of 2-Chloro-6-methyl-isonicotinic acid (1 g) in DMF (200 ml) at 25° C. was added DIPEA (2.9 mL) and TBTU (1.8 ml). After 5 min, dimethylamine (0.75 g) was added dropwise. This was stirred overnight. The reaction was added to water and extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuum. Flash:chromatography (9:1 to 2:8 gradient cyclohexane:EtOAc) afforded the title compound (320 mg). Rf=0.56 (1:1 cyclohexane:EtOAc)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](O)=[O:12].C(N(CC)C(C)C)(C)C.ClC(OCC(C)C)=O.[BH4-].[Li+].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11][OH:12]
Reactant: O=C(O)/C=C/c1cc(F)ccc1F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: OC/C=C/c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2E)-3-(2,5-difluorophenyl)acrylic acid (1 g, 5.43 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.8 mmol) in tetrahydrofuran (THF) was treated with isobutyl chloroformate (1.4 mL, 10.8 mmol) at room temperature. The reaction mixture was stirred for 30 minutes, and then filtered. The filtrate was cooled to 0° C. and 2M lithium borohydride (4.1 mL, 8.2 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes then at room temperature for 30 minutes. Ice and 1N hydrochloric acid were added to the reaction mixture to adjust the pH to 7. The aqueous layer was extracted with ethyl acetate twice. The combined organic extracts were dried over sodium sulfate and concentrated to dryness under reduced pressure. Silica gel chromatography with hexanes/ethyl acetate (3:2) afforded desired product, 750 mg (82%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[N:6][CH:7]=1.O1CCOCC1.[Na+].[I-:22].CN(C)CCN>CCOC(C)=O.[Cu]I>[I:22][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(Oc2cncnc2)nc1
Reactant: [I-]
Agent: [Cu]I
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Ic1ccc(Oc2cncnc2)nc1
Temperature: 110 °C

Procedure:
A mixture of 550 mg (2.18 mmol) 5-(5-bromopyridin-2-yloxy)pyrimidine and 2.5 mL 1,4-dioxane is charged with 42 mg (0.22 mmol) CuI, 650 mg (4.36 mmol) NaI and 50 μl (0.44 mmo) N,N-dimethylethylendiamine. The reaction mixture is stirred at 110° C. over night. The mixture is allowed to cool down to r.t. and diluted with EtOAc. The mixture is washed with 5% aq. ammonia solution and water. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo to yield the desired product without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:38]=[CH:37][C:15]3[C:16]4C([CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)=CN(C2N(C3C=CC(F)=CC=3F)N=CN=2)[N:17]=4)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2C3[N:48](CCOC=2C=1)[CH:47]=[C:46]([C:52]1[N:53]([CH:57]([CH3:59])[CH3:58])[N:54]=[CH:55][N:56]=1)N=3>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:38]=[CH:37][C:15]3[C:16]4[N:48]([CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:47]=[C:46]([C:52]2[N:53]([CH:57]([CH3:59])[CH3:58])[N:54]=[CH:55][N:56]=2)[N:17]=4)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(=O)OC(C)(C)C)C3)cc1OCC2

Procedure:
3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester was prepared similarly to 3-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylic acid tert-butyl ester from 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene and 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide. LCMS: RT=4.61 min, M+H+=451.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[CH:7][C:4]=1[CH:5]=[O:6].C(Cl)[Cl:18]>>[Cl:18][C:7]1[C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]=[O:6]
Reactant: ClCCl
Reactant: COc1cc(C=O)c(OC)c(OC)c1OC
Product: COc1c(Cl)c(C=O)c(OC)c(OC)c1OC
Reaction time: 1 h
Yield: 97 %

Procedure:
According to a general aryl chlorination procedure by Lopez-Alvarado,39 19 (0.767 g, 3.39 mmol) was dissolved in CH2Cl2 (10.0 mL) at room temperature and then SO2Cl2 (neat, 0.31 mL, 3.7 mmol) was added at room temperature. The reaction was stirred for 1 hour and monitored by 1H NMR for completion. The reaction was then diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered, and condensed. The resulting oil was then purified by flash column chromatography (1:4 Et2O:hexanes) to provide 20 (0.861 g, 3.30 mmol, 97%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].Cl[CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[O:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([O:14][CH2:16][C:17]3[CH:34]=[CH:33][CH:32]=[C:19]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:18]=3)[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1cc(=O)c2ccc(O)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1cc(=O)c2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Temperature: 0 °C

Procedure:
To 2-cyano-7-hydroxy-4-oxo-4H-1-benzopyran (11.87 mmoles) and 2-((3-chloromethylphenoxy)methyl)quinoline (11.87 mmoles) in dimethylsulfoxide (20 ml) is added powdered sodium hydroxide (0.475g). After one week the reaction mixture is poured into ice water and the resulting precipitate collected and purified by HPLC to give 2-cyano-7-(3-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran which is used directly in the next step.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[I:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1.Cl>CN(C=O)C>[I:11][C:12]1[CH:13]=[C:14]([CH3:20])[C:15]([O:19][CH:8]([CH3:10])[CH3:9])=[CH:16][C:17]=1[CH3:18]
Reactant: CC(C)I
Reactant: Cc1cc(I)c(C)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OC(C)C)c(C)cc1I
Temperature: 50 °C
Yield: 42 %

Procedure:
K2CO3 (1.23 g, 8.87 mmol) followed by 2-iodopropane (806 μL, 8.06 mmol) were added to a solution of 4-iodo-2,5-dimethyl-phenol (1.00 g, 4.03 mmol) in DMF (40 mL) and the solution was heated at 50° C. for 24 h. The mixture was then acidified with 1% aq HCl before it was extracted with EtOAc (3×100 mL). The combined organics were washed with 1 N NaOH (3×200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% ethyl acetate/hexanes) to provide 1-iodo-4-isopropoxy-2,5-dimethylbenzene (42%) as a yellow oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([N:21]1[C@@H:25]([CH2:26][CH2:27][OH:28])[CH2:24][O:23][C:22]1([CH3:30])[CH3:29])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]([N:21]1[C@@H:25]([CH2:26][CH:27]=[O:28])[CH2:24][O:23][C:22]1([CH3:30])[CH3:29])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OC[C@H](CCO)N1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(C)OC[C@H](CC=O)N1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A solution of dimethyl sulfoxide (6.39 g, 81.8 mmol) in dichloromethane (25 mL) as added at −70° C. to a solution of oxalyl chloride (5.59 g, 44.1 mmol) in dichloromethane (90 mL), then after 15 min a solution of (S)-4-(2-hydroxy-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid benzyl ester (8.79 g, 31.5 mmol) in dichloromethane (45 mL) was added dropwise. After 60 min triethylamine (15.9 g, 157 mmol) was added, then after 20 min the cooling bath was removed and the reaction mixture was stirred for 2 h. The reaction mixture was poured onto water and extracted five times with dichloromethane. The combined organic phases were dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/ethyl acetate 1:1) produced the title compound (8.52 g, 98%) as light yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]#[N:12].[C:13]([N:21]=[C:22]=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[C:11]([C:3]1[C:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]=2[S:10][C:2]=1[NH:1][C:22]([NH:21][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23])#[N:12]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#Cc1c(N)sc2c1CCOC2
Solvent: C1COCCO1
Product: N#Cc1c(NC(=O)NC(=O)c2ccccc2)sc2c1CCOC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of 2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carbonitrile (Example 146b) (400 mg, 2.22 mmol) in 1,4-dioxane (30 mL) was added benzoyl isocyanate (327 mg, 2.22 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitate was collected by filtration, washed with 1,4-dioxane, and dried in the air to give the title compound (577 mg, 80%) as a light yellow solid. NMR (400 MHz, DMSO-d6) δ 2.62 (t, J=5.2 Hz, 2H), 3.87 (t, J=5.2 Hz, 2H), 4.62 (s, 2H), 7.56-7.53 (m, 2H), 7.67-7.65 (m, 1H), 8.04-8.01 (m, 2H), 11.60 (brs, 1H), 12.13 (brs, 1H).
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27](Cl)=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1.Cl.Cl.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27]([N:42]3[CH2:41][CH2:40][N:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[Cl:32])[CH2:44][CH2:43]3)=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:16])=[O:17])=[CH:12]2)=[CH:7][CH:6]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2c1
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N3CCN(c4ccccc4Cl)CC3)cc2c1
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
The thus obtained N2 -(7-methoxy-2-naphthalene-sulfonyl)-L-arginyl chloride (2.4 g) is immediately added to a solution of 1.64 g (0.00608 mole) 1-(2-chlorophenyl)piperazine dihydrochloride and 2.56 g (0.0253 mole) triethylamine in 50 ml chloroform under ice chilling. After 10 minutes, the mixture is brought to room temperature, and allowed to stand overnight. Then the reaction mixture is washed with water and the solvent is distilled off. The residue is washed with ethyl ether and dissolved in a 30%-ethanol/50 ml water mixture, and made basic with a 2N sodium hydroxide aqueous solution to pH 10. Thus an oily substance is deposited and is crystallized on standing. The crystals are collected by filtration, dried, and recrystallized from 20 ml THF, and 0.83 g of 1-[N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl]-4-(2-chlorophenyl)piperazine is obtained. Yield 28%. m.p. 219°~221° C. (decomp.) IR(KBr): 3330, 1625, 1480 cm-1.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1C#N>OS(O)(=O)=O>[OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])=[CH:18][CH:19]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[CH:7]=1
Reactant: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4O)cc3)csc2[nH]c1=O
Agent: O=S(=O)(O)O
Product: O=c1cc(O)c2c(-c3ccc(-c4ccccc4O)cc3)csc2[nH]1
Temperature: 25 °C

Procedure:
4-hydroxy-3-(2′-hydroxy-1,1′-biphenyl-4-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.040 g) in 40% H2SO4 (20 mL) was heated at reflux for 16 hours, cooled to room temperature and quenched with 50% NaOH (till pH=2). It was then extracted with ethyl acetate (3×70 mL), organic extracts washed with water (25 mL), brine (15 mL), concentrated and purified on a RP-HPLC system to afford the title compound. MS (ESI) m/e 334.0 (M−H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 10.96 (s, 1H), 9.52 (s, 1H), 7.53 (d, J=8.59, 2H), 7.47 (d, J=7.98, 2H), 7.29 (dd, J=7.67, 1.84, 1H), 7.16 (m, 1H), 7.04 (s, 1H), 6.96 (d, J=7.97, 1H), 6.89 (m, 1H), 5.76 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:44][O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:46]([O:45][N:44]=[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:12][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:42][C:6]=2[N:7]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)[C:8]1=[O:22])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NOCc1ccccc1
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCc1cc2c(=O)n(CC(=NOCc3ccccc3)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), [(aminooxy)methyl]benzene hydrochloride (0.07 g), pyridine (10 mL) and ethanol (10 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.098 g, 42%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[N:12][C:11]=2[O:19][CH2:20][CH:21]([F:23])[F:22])=[CH:4][CH:3]=1.C(Cl)Cl.CCO>C1COCC1.[Ni]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12][C:11]=2[O:19][CH2:20][CH:21]([F:22])[F:23])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1cc([N+](=O)[O-])cnc1OCC(F)F
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cnc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)c1

Procedure:
Prepared analogously to Example 4b from N-(4-bromophenyl)-2-(2,2-difluoroethyl)oxy-5-nitronicotinic acid amide and Ra-Ni in THF. Yield: (quantitative). MS [m+H]+=372 (Br-isotope pattern); TLC: Rf=0.60 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][N:11]([Si](C(C)C)(C(C)C)C(C)C)[C:8]=3[N:9]=[CH:10][C:5]2=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[N:3]=1.C1C(=O)N([Br:41])C(=O)C1>C(Cl)Cl>[Br:41][C:12]1[NH:11][C:8]2[N:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][C:4]=3[C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C:7]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)n12
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3[nH]c(Br)cc3n12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
To a solution of 2-(4-(1-methyl-6-(triisopropylsilyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.755 g, 1.63 mmol, Preparation #AX.1) in DCM (16.3 ml) at about −20° C. was added NBS (0.462 g, 2.59 mmol). The resulting suspension was allowed to stir at about −20° C. for about 15 min. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (40 g silica gel column; gradient elution with 0 to 50% EtOAc/heptane) to give 2-(4-(7-bromo-1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.11 g, 18%). LC/MS (Table 2, Method a) Rt=2.41 min; MS m/z 385 (M+H)+. Syk IC50=B.