Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[CH3:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: Cc1c(Br)cccc1CBr
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1c(Br)cccc1Cn1ncc2ccccc21
Temperature: 80 °C
Reaction time: 18.25 h

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-2-methylbenzene (prepared according to the procedures reported in US Pat. Appl. 2006/0173183, 250 mg, 0.947 mmol), 1H-indazole (112 mg, 0.947 mmol) and potassium carbonate (131 mg, 0.947 mmol) in acetonitrile (5 mL) was heated with stirring at 80° C. After 18.25 h, the mixture was cooled to rt, diluted with water and extracted three times with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 65:35 hexane-EtOAc) to provide 1-(3-bromo-2-methylbenzyl)-1H-indazole as an oil which crystallized on standing (Intermediate 31-1, 74 mg, 26%). 1H NMR (400 MHz, chloroform-d) δ 8.06 (1H, d, J=0.9 Hz), 7.76 (1H, dt, J=8.1, 1.0 Hz), 7.48 (1H, d, J=7.9 Hz), 7.30-7.37 (1H, m), 7.26-7.30 (1H, m), 7.16 (1H, ddd, J=8.0, 6.8, 1.0 Hz), 6.93 (1H, t, J=7.8 Hz), 6.70 (1H, d, J=7.7 Hz), 5.61 (2H, s), 2.45 (3H, s). Mass spectrum m/z 301, 303 (M+H)+. Also obtained was 2-(3-bromo-2-methylbenzyl)-2H-indazole as a pale yellow gum (Intermediate 31-2, 164 mg, 58%). 1H NMR (400 MHz, chloroform-d) δ 7.68-7.76 (2H, m), 7.54-7.63 (2H, m), 7.28 (1H, ddd, J=8.2, 7.2, 1.1 Hz), 6.97-7.10 (3H, m), 5.63 (2H, s), 2.37 (3H, s). Mass spectrum m/z 301, 303 (M+H)+.
Reaction SMILES: [C:1]1(OB(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CO.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:35][CH:32]1[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([C:19]#[C:18][C:15]3[CH:14]=[CH:13][C:12]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:17][N:16]=3)=[CH:21][CH:22]=2)[CH2:30][CH2:31]1
Reactant: CC1CCN(CCOc2ccc(C#Cc3ccc(Br)cn3)cc2)CC1
Reactant: OB(O)Oc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccccc4)cn3)cc2)CC1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
Under an argon atmosphere 30 mg (0.25 mmol) phenylboric acid are added to a solution of 100 mg (0.25 mmol) 5-bromo-2-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine, 0.25 mL (0.50 mmol) of a 2 M Na2CO3 solution and 4 mg (0.01 mmol) Pd(dppf)Cl2 in 5 mL 1,4-dioxane and 2 mL MeOH. The reaction mixture is stirred for 3 days at 90° C. The reaction mixture is diluted with EtOAc and the organic phase is washed with 40 mL water and finally with saturated NaCl solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out using HPLC-MS and by column chromatography on silica gel (gradient: DCM/MeOH/NH3 95:5:0.5 to DCM/MeOH/NH3 9:1:0.1).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]3)[C:10]2=[O:24])=[C:6]([F:27])[CH:5]=1.[C:28]([O:34][CH2:35]Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].Cl>CS(C)=O.O>[Br:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21](=[O:22])[N:20]([CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:19](=[O:23])[NH:18]3)[C:10]2=[O:24])=[C:6]([F:27])[CH:5]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OCN1C(=O)NC2(C1=O)C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Reaction time: 0.08 h

Procedure:
Ethanolic potassium hydroxide solution (1 M; 5.2 ml) was added to a solution of 1'-(4-bromo-2-fluorobenzyl)-spiro-[imidazolidine-4,3'-indoline]-2,2',5-trione (2.0 g.) in dimethyl sulphoxide (10 ml.). The solution was stirred for 5 minutes and then chloromethyl pivalate (0.75 g.) was slowly added. After the addition was completed, the reaction mixture was further stirred for 16 hours; and then poured into water (100 ml.). The aqueous mixture was carefully acidified (concentrated hydrochloric acid). The precipitate which formed was washed with water, air dried and recrystallised twice from 2-propanol to give 1'-(4-bromo-2-fluorobenzyl)-1-(pivaloyloxymethyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, as a white solid (0.75 g.), m.p. 220°-222° C.
Reaction SMILES: [CH:1]([NH2:3])=O.[CH3:4][O:5][C:6]([C:8]1[CH:21]=[C:20]([NH2:22])[C:19]2[C:18](=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:24])[C:10]=2[C:9]=1[NH2:25])=[O:7].[C-]#N.[Na+].[Cl-].[NH4+].[OH-].[Na+]>O.CO>[CH3:4][O:5][C:6]([C:8]1[C:21]([C:1]#[N:3])=[C:20]([NH2:22])[C:19]2[C:18](=[O:23])[C:17]3[C:12]([C:11](=[O:24])[C:10]=2[C:9]=1[NH2:25])=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:7]
Reactant: COC(=O)c1cc(N)c2c(c1N)C(=O)c1ccccc1C2=O
Reactant: NC=O
Agent: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(N)c2c(c(N)c1C#N)C(=O)c1ccccc1C2=O
Temperature: 50 °C

Procedure:
A mixture of 500 parts of formamide and 80 parts of methanol is prepared and 80 parts of 1,4-diamino-anthraquinone-2-carboxylic acid methyl ester and 60 parts of sodium cyanide are introduced, whilst stirring. The mixture is heated to 50° C. and a gentle stream of air is passed through it, whilst stirring. Stirring is continued until a thin layer chromatogram indicates that no starting material is left; this is generally the case after 5 hours. After cooling, the reaction mixture is added to 1,000 parts of water and 500 parts of ice, whilst stirring, and 200 parts of ammonium chloride are added to buffer the sodium hydroxide formed. The suspension is subsequently stirred whilst passing air through it, and the product is filtered off, washed neutral with warm water and rinsed with a little methanol. After drying, 81.5 parts of 1,4-diamino-2-cyano-anthraquinone-3-carboxylic acid methyl ester are obtained; melting point 914°-198° C.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]([CH2:10]P(OC)(OC)=O)=[O:9].[CH2:17]([C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[CH2:18][CH:19]=[CH2:20]>O1CCCC1>[CH2:17]([C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](/[CH:39]=[CH:10]/[C:8]([O:7][CH3:6])=[O:9])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:25][CH2:26]1)[CH2:18][CH:19]=[CH2:20]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: C=CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=O)cc3)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[C@H]1CC[C@H](c2ccc(-c3ccc(/C=C/C(=O)OC)cc3)cc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
27.6 ml of a 1.6N butyllithium solution were added dropwise at 0° C. within 10 minutes to a solution of 6.4 ml of trimethyl phosphonoacetate in 50 ml of dry tetrahydrofuran. The mixture was stirred at 0° C. for 1.5 hours and thereafter a solution of 11.5 g of crude trans-4'-[4-(3-butenyl)cyclohexyl]biphenyl-4-carboxaldehyde in 50 ml of dry tetrahydrofuran was added dropwise within 5 minutes at the same temperature. Subsequently, the mixture was warmed slowly to room temperature and left to react for 15 hours. The reaction mixture was then partitioned between methylene chloride and 1N hydrochloric acid and the organic phase was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated. Chromatography on silica gel with ethyl acetate/hexane (1:9) and subsequent repeated recrystallization from hexane/ethyl acetate gave methyl trans-(E)-3-{4'-[4-(3-butenyl)cyclohexyl]biphenyl-4-yl}acrylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@H:16]([C:24]([NH2:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([CH:16]1[NH:15][C:11]2([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[NH:26][C:24]1=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)C(Cc1ccccc1)N2

Procedure:
N-tert-Butyloxycarbonylpiperidone (6.0 g, 29.8 mmol) was added to a solution of phenylalaninamide (4.9 g, 29.8 mmol) in dry EtOH (20 ml) and the mixture was heated under reflux for 2.5 h. The solvent was removed by distillation, and the tert-butyl 3-benzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (10.8 g) was used in the following reaction without further workup.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:24])[CH:11]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:24])[C@@H:11]([NH2:16])[CH2:12][CH2:13][CH2:14][CH2:15][C@H:8]2[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC2CCCCC(NC(=O)OC(C)(C)C)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@@H]2CCCC[C@H](N)C(=O)N21
Reaction time: 2 h

Procedure:
6-tert-butoxycarbonylamino-5-oxo-decahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 17, (272 mg, 0.8 mmol) is dissolved in dichloromethane (5 mL) and treated trifluroacetic acid (5 mL). The solution is stirred for two hours then the solvent removed in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[C:17]4[CH:30]=[CH:29][S:28][C:18]=4[C:19](=[O:27])[NH:20][C:21]=3[CH:22]=[CH:23][C:24]=2[O:25]C)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.BrB(Br)Br>>[OH:25][C:24]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:27])[C:18]3[S:28][CH:29]=[CH:30][C:17]=3[C:16]=2[C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: NS(=O)(=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 92.2 %

Procedure:
Following General Procedure F, N-tert-butyl-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (4.3 g, 9.9 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 48 mL, 48 mmol) to afford the desired product (3.4 g, 94%) as a light red solid: 1H NMR (300 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.12 (s, 1H), 7.96-7.95 (m, 2H), 7.76 (d, J=5.4 Hz, 1H), 7.48-7.47 (m, 4H), 7.41 (d, J=8.9 Hz, 1H), 7.18 (d, J=8.9 Hz, 1H), 5.91 (d, J=5.4 Hz, 1H); ESI MS m/z 373 [C17H12N2O4S2+H]+; HPLC 98.1% (AUC), tR=10.29 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([NH:13][N:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([NH:13][NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(=O)NN=C1CCN(c2ccncc2)CC1)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CC(=O)NNC1CCN(c2ccncc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
The resultant 1-[(tert-butoxycarbonyl)sarcosinyl]-2-[1-(4-pyridyl)-4-piperidinylidene]hydrazine (1.0 g) was dissolved in methanol (20 ml) and treated with acetic acid (665 mg) with cooling on ice, followed by sodium cyanoborohydride (261 mg) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate and brine, dried and concentrated to obtain 1-[(tert-butoxycarbonyl)sarcosinyl]-2-[1-(4-pyridyl)-4-piperidinyl]hydrazine (1.0 g) as a colorless oil.
Reaction SMILES: C(OC1C(OC)=CC=C(I)C=1O)C1C=CC=CC=1.C(N1C=C(C#C)C=N1)C1C=CC=CC=1.COC1C=C(I)C=C(OC)C=1OC.[CH2:46]([N:53]1[CH:57]=[C:56]([C:58]2[O:59][C:60]3[C:80]([O:81]CC4C=CC=CC=4)=[C:79]([O:89][CH3:90])[CH:78]=[CH:77][C:61]=3[C:62]=2[C:63]([C:65]2[CH:70]=[C:69]([O:71][CH3:72])[C:68]([O:73][CH3:74])=[C:67]([O:75][CH3:76])[CH:66]=2)=[O:64])[CH:55]=[N:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CCCCCC.C(OCC)(=O)C>[CH2:46]([N:53]1[CH:57]=[C:56]([C:58]2[O:59][C:60]3[C:80]([OH:81])=[C:79]([O:89][CH3:90])[CH:78]=[CH:77][C:61]=3[C:62]=2[C:63]([C:65]2[CH:66]=[C:67]([O:75][CH3:76])[C:68]([O:73][CH3:74])=[C:69]([O:71][CH3:72])[CH:70]=2)=[O:64])[CH:55]=[N:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COc1cc(C(=O)c2c(-c3cnn(Cc4ccccc4)c3)oc3c(OCc4ccccc4)c(OC)ccc23)cc(OC)c1OC
Agent: C#Cc1cnn(Cc2ccccc2)c1
Agent: COc1cc(I)cc(OC)c1OC
Agent: COc1ccc(I)c(O)c1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(C(=O)c2c(-c3cnn(Cc4ccccc4)c3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 8 h

Procedure:
Application of the general procedure to 2-benzyloxy-6-iodo-3-methoxy-phenol, 1-benzyl-4-ethynyl-1H-pyrazole and 3,4,5-trimethoxy-iodo-benzene (NB—the initial coupling proceeded slowly and was continued overnight) and silica-gel flash chromatography (eluent=40% ethyl acetate in hexane) gave a mixture of the title compound, [2-(1-benzyl-1H-pyrazol-4-yl)-7-benzyloxy-6-methoxy-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone and the corresponding non-carbonyl inserted derivative. This mixture was again subjected to silica-gel flash chromatography (sequential elution—2% diethyl ether in DCM, 10%). Concentration of the first eluted fractions afforded a mixture of the 7-benzyloxy derivative and the non-carbonyl inserted material and was used in subsequent chemistry. The later fractions gave the title compound (2% yield) as a pale yellow solid. An analytical sample was obtained by recrystallisation from DCM and hexane. 1H-NMR (CDCl3) δ 8.08 (s, 1H), 8.03 (s, 1H), 7.36-7.27 (m, 3H), 7.22-7.19 (m, 2H), 7.10 (s, 2H), 6.80 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 5.28 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.74 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[NH:27][CH2:26][CH2:25][N:10]2[C:11](=[O:24])[C:12]2[N:13]([C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:16][CH:17]=2)[CH2:14]3)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[C:18]([C:15]1[N:13]2[CH2:14][C:9]3([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:27][CH2:26][CH2:25][N:10]3[C:11](=[O:24])[C:12]2=[CH:17][CH:16]=1)#[CH:19]
Reactant: COc1ccc(C23Cn4c(C#C[Si](C)(C)C)ccc4C(=O)N2CCN3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc2n1CC1(c3ccc(OC)cc3)NCCN1C2=O
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 10a-(4-methoxyphenyl)-8-[(trimethylsilyl)ethynyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (84 mg, 0.22 mmol) in methanol (5 mL) was added potassium carbonate (60 mg, 0.43 mmol). The suspension was stirred at room temperature until the reaction was complete (monitored by LCMS). The solid was suspended in CH2Cl2, filtered and concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, 12 g cartridge, CH2Cl2 3CV, gradient 0-10% MeOH in CH2Cl2 10CV). To give 8-Ethynyl-10a-(4-methoxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a yellow solid (60 mg, yield 89%). ESI-MI m/z [M+H]+ 308.0.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[CH2:14]([NH2:17])[CH2:15][NH2:16]>O1CCCC1>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:16][CH2:15][CH2:14][NH2:17])#[N:2]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: NCCN
Solvent: C1CCOC1
Product: N#Cc1ccccc1OCC(O)CNCCN
Reaction time: 16 h

Procedure:
A solution of 1-(2-cyanophenoxy)-2,3-epoxypropane (93.3 g.) in tetrahydrofuran (700 ml.) is added dropwise during 5 hours to stirred ethylenediamine (600 g.) and the mixture is stirred for a further 16 hours and then evaporated to dryness under reduced pressure. The residue is twice dissolved in water (500 ml.) and then evaporated to dryness, and then twice dissolved in toluene (500 ml.) and then evaporated to dryness. There is thus obtained as residue 1-(2-cyanophenoxy)-3-(β-aminoethylamino)-2-propanol.
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:3]=1[C:24]#[N:25].[CH2:26]([Sn](CCCC)(CCCC)CCCC)[C:27](=[CH2:29])[CH3:28].[K].[Li+].[Cl-]>CN(C=O)C.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>[CH3:28][C:27](=[CH2:26])[CH2:29][C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:3]=1[C:24]#[N:25]
Reactant: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(I)c3C#N)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [K]
Solvent: CN(C)C=O
Product: C=C(C)Cc1nc2n(c1C#N)CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 110 °C

Procedure:
To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carbonitrile (example 221) (107 mg, 0.239 mmole) in DMF (4 mL) are added potassium methallyltributyltin (331 mg, 0.95 mmole), Pd(PPh3)4 (28 mg, 0.025 mmole), LiCl (51 mg, 1.30 mmole). The flask is evacuated and filled with argon. The reaction mixture is heated at 110° C. for 5 hours. AcOEt and water are added, as well as a 10% KF solution. The aqueous phase is extracted with AcOEt. The organic phase is washed with 0.5N HCl. The HCl phase is made alkaline with 1H NaOH and the aqueous phase is extracted with AcOEt. The organic phase is dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (100:0) to (95:5) to give 2-(2-methylallyl)-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carbonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][CH:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC(=O)C[C@H]1C(O)=O)=O)(C)(C)C.NOC[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH2:10][CH:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(CON)cc1
Agent: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Product: COc1ccc(CON=C2CC(C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 85 %

Procedure:
The same method as employed in the preparation of Intermediate 7, but starting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (Intermediate 1) and 1[(aminooxy)methyl]-4-methoxy-benzene (Intermediate 10) gave the title compound as a gum in a 85% yield.
Reaction SMILES: [C:1]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=O)([O:3][CH2:4][CH3:5])=[O:2]>CO.[BH4-].[Na+]>[CH2:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1Cc2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1=Cc2ccccc2C1

Procedure:
2-Carbethoxy-1-indanone was dissolved in dry methanol at room temperature, to which sodium borohydride was added in three lots while the reaction mixture was kept stirring. The reaction mixture was further stirred for 30 minutes, after which the solid was filtered and the filtrate was evaporated to dryness. The residue was dissolved in dry benzene, to which catalytic amount of p-toluenesulfonic acid was added and the reaction mixture was stirred for one hour. The p-toluenesulfonic acid was filtered off and the filtrate was concentrated to yield ethyl indene-2-carboxylate. The ethyl indene-2-carboxylate was dissolved in methanol and 1.0 equivalent of aqueous sodium hydroxide solution was added and the reaction mixture was kept stirring for overnight. The next day, the reaction was terminated by evaporating the methanol, followed by diluting the residue with water, brought to neutral pH and the precipitated indene-2-carboxylic acid was filtered. NMR: (CDCl3):δ:3.75 (s, 2H, benzylic CH2); 7.4-7.7 (m, 4H, Ar-H); 7.95 (s, 1H, olefinic H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:18]S(C(C)(C)C)=O)[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].Cl.O1CCOCC1>CO>[NH2:18][CH:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCC(N)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of methyl 4-(2,6-dimethoxyphenyl)-4-(1,1-dimethylethylsulfinamido)butanoate (7.750 g; 21.68 mmol) in MeOH (70 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (10.9 ml; 43.60 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate as a dark-yellow/brown oil. LC-MS (conditions A): tR=0.45 min.; [M+H]+: 254.40 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][S:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:35].ClCCl.CO.ClCl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][S:27](=[O:35])[CH2:26]1)=[O:24])[C:5]([NH:7][CH:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: CC(NC(=O)c1ccc(C(=O)N2CCSC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: ClCl
Solvent: CO
Solvent: ClCCl
Product: CC(NC(=O)c1ccc(C(=O)N2CCS(=O)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 46 %

Procedure:
Prepared analogously to Example 85 from rac.-3-chloro-N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]4-(thiazolidin-3-ylcarbonyl)benzamide and 3-chloroperoxybenzoic acid in dichloromethane/glacial acetic acid. Yield: 46%; Rf value: 0.20 (silica gel; dichloromethane/methanol=9:1); C20H18Cl2N4O3S (465.36); mass spectrum: (M+H)+=465/467 (chlorine isotope) and (M−H)−=463/465 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1([F:31])[CH2:21][CH2:20][C:19]([CH2:29][NH2:30])([C:22]2[CH:23]=[N:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:19]1([C:22]2[CH:23]=[N:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:20][CH2:21][C:16]([F:15])([F:31])[CH2:17][CH2:18]1)=[O:6]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cc(C(F)(F)F)ccc1Cl

Procedure:
From 2-chloro-5-trifluoromethylbenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=451.1, tR (minutes, Method C)=1.15