Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([N:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:29])[CH2:26][C:27]#[N:28])[C@H:21]([CH3:30])[CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>C1COCC1>[C:11]([N:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:29])[CH:26]([C:32]2[S:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)[C:27]#[N:28])[C@H:21]([CH3:30])[CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2s1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(C#N)c1nc2ccccc2s1
Reaction time: 10 h
Yield: 6.5 %

Procedure:
NaHMDS (1.48 ml, 1M in THF) was added into a solution of (R)-N-benzoyl-3-methyl-N′-(2-cyano-acetyl)piperazine (190 mg) and 2-chlorobenzothiazole (100 mg) in THF (10 ml). After the reaction was stirred for 10 hours, 4 ml of solution was separated and quenched with MeOH. After solvents were removed under vaccum, the residue was purified using Shimadzu automated preparative HPLC System to give (R)-N-(benzoyl)-3-methyl-N′-[(benzothiazol-2-yl)-2-cyanoacetyl]-piperazine (15.4 mg).
Reaction SMILES: [C:1]1([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C:7]2([CH2:10][NH2:11])[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-phenylcyclopropanecarbonitrile (50 g, 0.34 mol, 1 eq.) in tetrahydrofuran (500 mL, 0.7 M) at 0° C. was added lithium aluminum hydride (23 g, 0.35 mol, 1.03 eq.). The reaction mixture was stirred at 0° C. for one hour and then at reflux for one hour. The reaction mixture was then cooled down and quenched with water (23 mL) and a 15% aqueous sodium hydroxide solution (69 mL). The mixture was filtered and concentrated in vacuo to afford #*1 (36 g, 72%). LC-MS: m/z 148.1 [M+H+], retention time=0.86 minutes; 1H NMR (400 MHz, CDCl3) δ 7.2-7.4 (m, 5H), 2.78 (s, 2H), 1.19 (br s, 2H), 0.72-0.84 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[CH:30]=[C:29]([C:9]3[CH:8]=[N:7][C:6]4[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=3)[CH:28]=[N:27]2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Clc1cnc2cccc(Br)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4cccc(Br)c4n3)cn2)CC1
Temperature: 80 °C

Procedure:
A microwave tube is charged with 8-Bromo-2-chloro-quinoxaline (Step 1.4, 1 g, 4.11 mmol), 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.74 g, 3.70 mmol), K3PO4 (2.67 g, 12.3 mmol) and of PdCl2(PPh3)2 (88.2 mg, 0.123 mmol). After several cycles of vacuum/purge with argon, a mixture of 5 ml of DMA and 220 μl deionized water is added. The reaction mixture is then heated to 80° C. for 3 h. After cooling, the suspension is poured onto de-ionized water and diluted with EtOAc. The phases are separated and the aqueous phase re-extracted twice with EtOAc. The combined organic phases are washed with saturated brine and dried over Na2SO4. After filtration, the mixture is concentrated in vacuo. The residue is purified by chromatography on a 80 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient hexanes:EtOAc from 1:0=>0:1) to afford the title compound as a yellow foam, Rt=1.350 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 458 (M+1, 79Br)+.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:13][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CNc1ccccc1N
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)c1ccc(-c2nc3ccccc3n2C)cc1
Temperature: 145 °C
Yield: 65 %

Procedure:
A mixture of methyl 4-formylbenzoate (5.0 g, 0.03 mol) and N-methyl-1,2-phenylene diamine (3.7 g, 0.03 mol) in nitrobenzene was heated at 140-150° C. overnight, cooled to room temperature, filtered and the filtercake washed with hexane. The combined filtrates were evaporated to dryness under reduced pressure. The resultant residue was purified by flash chromatography (silica, CHCl3:MeOH 95:5) to afford the title compound in 65% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, CDCl3): 8.2 (d, J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 7.83 (s, 1H), 7.37 (m, 1H), 7.35 (m, 2H), 3.96 (s, 3H), 3.9 (s, 3H). LCMS (ESI+) 267 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[S:12])=[CH:6][CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[S:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(NC(=S)NCc2ccncc2)cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(NC(=S)NCc2ccncc2)cc1
Reaction time: 8 h

Procedure:
To a mixture of 5.76 gms. (0.02 mole) of 1-(p-nitrophenyl)-3-(4-pyridylmethyl)-2-thiourea, (Example 2, supra.), 200 ml. of ethanol and 65 ml. of hydrazine hydrate is added with stirring 0.5 grams of 5 percent palladium-on-carbon in 50 ml. of ethanol. The resulting mixture is allowed to stand overnight at room temperature and then refluxed for 2 to 3 hours. The hot reaction mixture is then filtered and the filtrate evaporated to remove solvents. The residue is 1-(p-aminophenyl)-3-(4-pyridylmethyl)-2-thiourea.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[O:3][C:4]([CH:6]=[CH2:7])=[CH2:5].[C:10]1(=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[O:3][C:4]1[CH2:5][C:10]2([CH2:12][CH2:11]2)[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][CH:6]=1
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: CCOC(=O)C=C1CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC=C(O[Si](C)(C)C)CC12CC2
Temperature: 130 °C

Procedure:
2-(Trimethylsiloxy)-1,3-butadiene (900 mg, 6.33 mmol) and ethyl cyclopropylideneacetate (2195 mg, 17.40 mmol) were combined in toluene (3 ml) and heated to 130° C. for 14 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo to yield ethyl 7-[(trimethylsilyl)oxy]spiro[2.5]oct-6-ene-4-carboxylate that was used without further purification in the subsequent reaction.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([C:13]4([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)cc1

Procedure:
[2-(4-Dimethylamino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-(dimethylamino)phenylboronic acid following general procedures as described in these Examples. MP 272-274° C., M+H=363.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][N:11]=1>O>[C:20]1([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:7][C:4]3[CH:5]=[CH:6][C:1]([NH2:8])=[CH:2][CH:3]=3)=[N:11][N:12]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(N)cc1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Solvent: O
Product: Nc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 110 °C

Procedure:
Benzene-1,4-diamine (0.337 g, 3.12 mmol) and 1-chloro-4-phenylphthalazine (0.500 g, 2.08 mmol) were treated with 7.5 mL 2-BuOH in a sealed tube and heated to 110° C. The reaction quickly became a solid, yellow mass. After several hours, the reaction was cooled and diluted with water. The slurry was then partitioned between DCM and 1N NaOH. The aqueous layer was extracted into DCM (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography, ISCO, 40 g, 0-10% MeOH/MC to give N1-(4-phenylphthalazin-1-yl)benzene-1,4-diamine as an orange-brown solid. MS m/z=313 [M+H]+. Calc'd for C20H16N4: 312.4.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([OH:12])(=O)[C:8]([CH3:10])=[CH2:9]>ClCCl>[CH3:1][C:2]1[S:3][C:4]2[C:7](=[O:12])[CH:8]([CH3:10])[CH2:9][C:5]=2[CH:6]=1
Reactant: C=C(C)C(=O)O
Reactant: Cc1cccs1
Solvent: ClCCl
Product: Cc1cc2c(s1)C(=O)C(C)C2
Temperature: 80 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
A solution of 100 g of 2-methylthiophene (1.02 mol) and 104 ml of methacrylic acid (1.22 mol) in 200 ml of dichloromethane was added dropwise within 30 minutes at 80° C. to 1000 g of super-PPA. Afterwards, the reaction mixture was stirred at 80° C. for 3 hours. The dark red mixture was poured into 1000 g of crushed ice and stirred until the polyphosphoric acid had completely dissolved. The aqueous phase was extracted twice with 400 ml each time of a dichloromethane/hexane solvent mixture (30 parts by volume/70 parts by volume). The combined organic phases were washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over magnesium sulfate. After removal of the solvents on a rotary evaporator, 136 g of crude product were obtained. The distillation of the crude product (90° C., 0.1 torr) gave 76 g (46%) of product.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
To a solution of methyl 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (70 mg, 0.19 mmol) in tetrahydrofuran (2 ml) and methanol (1 ml) was added 4N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for 24 hr. 1N Hydrochloric acid was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and dried in vacuo to give 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (59 mg, yield 85.2%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-:16].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:16][CH:12]([CH2:13][CH3:14])[C:11]([C:8]1[S:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[CH:9]=1)=[O:15]
Reactant: CCCC(=O)c1cc2c(Cl)cccc2s1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CCC(Br)C(=O)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 66 h
Yield: 148.6 %

Procedure:
A mixture of 1-(4-chlorobenzo[b]thiophen-2-yl)butan-1-one (0.93 g), phenyltrimethylammonium tribromide (1.47 g) and tetrahydrofuran (20 ml) was stirred under nitrogen at ambient temperature for 66 hours, then it was filtered and diluted with water (50 ml). The product was extracted into dichloromethane (3×30 ml), the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl)butan-1-one (1.07 g) which was used without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([CH3:28])=[CH:30][CH:31]=3)=[O:25])[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(CN)cc1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Product: Cc1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc32)cc1

Procedure:
Example 126 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate Example 117) and 4-methylbenzylamine to give the title compound (0.010 g)
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:25][CH2:24][CH2:23][CH2:22][O:21][CH3:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Reactant: COCCCN
Solvent: Cc1ccccc1
Product: COCCCNc1nc2cc(Cl)c(Cl)cc2nc1-c1ccccn1
Yield: 76.9 %

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.50 g) and 3-methoxy-propylamine (0.28 g) in toluene (20 mL) was refluxed under nitrogen for 16 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was recrystallized from methanol and water to give the product as a yellow solid (0.45 g); mp 99.5-100.5° C.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-])=O.C([Sn](CCCC)(CCCC)[C:15]1[N:16]=[CH:17][S:18][CH:19]=1)CCC>>[S:18]1[CH:19]=[C:15]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[NH2:7])[N:16]=[CH:17]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: Nc1ccsc1-c1cscn1

Procedure:
This amine was prepared from 2-chloro-3-nitrothiophene using Protocols E and F except that 4-(tributylstannyl)thiazole was used. Method[1], MS(ESI) 183.0 [M+H], Retention time=0.518 min.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[CH:15]=1)(=[O:4])=[O:3].[OH-].[NH4+:17]>O1CCCC1>[NH2:17][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[CH:15]=1)(=[O:4])=[O:3]
Reactant: CC1(C)Cc2cc(S(=O)(=O)Cl)ccc2O1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(S(N)(=O)=O)ccc2O1

Procedure:
In a manner similar to Step B of Example 9, the reaction of 9.0 g (0.036 mole) of 5-chlorosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran with 60 mL of an aqueous 29% ammonium hydroxide solution in 70 mL of tetrahydrofuran produced 8.0 g of 5-aminosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran as a solid (mp 157°-160° C.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=S(Cl)Cl.O.C([O-])([O-])=O.[Na+].[Na+].[CH3:26][CH2:27]O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:26][CH3:27])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1cnc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Yield: 64 %

Procedure:
To a solution of the compound obtained in stage A (15 g, 79 mmol) in EtOH (500 ml) was added dropwise SOCl2 (40 mL). The resulting mixture was stirred under reflux during 12 hours. After adding water (200 mL), the pH was adjusted to 7.0 with 20% aqueous Na2CO3. The aqueous solution was extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to afford 11 g (yield: 64%) of the product of molecular formula C12H11NO3. Aspect: pale brown powder.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:64]1([CH2:67][N:68]2[CH2:74][CH2:73][CH2:72][N:71]([CH:75]3[CH2:80][CH2:79][CH:78]([NH2:81])[CH2:77][CH2:76]3)[CH2:70][CH2:69]2)[CH2:66][CH2:65]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:81][CH:78]5[CH2:77][CH2:76][CH:75]([N:71]6[CH2:72][CH2:73][CH2:74][N:68]([CH2:67][CH:64]7[CH2:65][CH2:66]7)[CH2:69][CH2:70]6)[CH2:80][CH2:79]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC(N2CCCN(CC3CC3)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCC(N3CCCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (88 mg, 0.2 mmol, 1 eq), DIPEA (70 μl, 0.4 mmol, 2 eq) and TBTU (72 mg, 0.24 mmol, 1.2 eq) were added to 2 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-(cyclopropylmethyl)-1,4-diazepan-1-yl)cyclohexanamine (Intermediate 14) (60 mg, 0.24 mmol, 1.2 eq). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-(4-(4-(cyclopropylmethyl)-1,4-diazepan-1-yl)cyclohexyl)-3-methoxybenzamide as a mixture cis and trans isomers (off-white solid, 67 mg, 50%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH:11]([C:13]1[CH:20]=[CH:19][C:17]([OH:18])=[C:15]([OH:16])[CH:14]=1)[OH:12])C)C1C=CC=CC=1.[H][H]>O.S(=O)(=O)(O)O.[Pd]>[CH3:1][NH:8][CH2:10][CH:11]([C:13]1[CH:20]=[CH:19][C:17]([OH:18])=[C:15]([OH:16])[CH:14]=1)[OH:12]
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)CC(O)c1ccc(O)c(O)c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O
Product: CNCC(O)c1ccc(O)c(O)c1

Procedure:
Benzyladrenaline 2 is dissolved in about 10 ml of water and about 5 ml of 18% sulfuric acid (pH: about 5.5), about 50 mg of palladium-charcoal (10%) are added and the mixture is hydrogenated at about 60° C. under 2 bar of hydrogen pressure. It is then evaporated down to about half its volume, about 20 ml of methanol are added and the mixture is cooled. The crystalline product (adrenaline sulphate 3) is filtered off and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](N)[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.N([O-])=O.[Na+].[FH:29]>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:29])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2cccc(N)n2)CC1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@H](c2cccc(F)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Batch 2: To a solution of trans-4-(6-amino-pyridin-2-yl)-cyclohexanecarboxylic acid ethyl ester (0.25 g, 1.0 mmol) in 70% hydrogen fluoride in pyridine (2.4 ml, 92 mmol) was added solid sodium nitrite (0.076 g, 1.1 mmol) at 0-5° C. The cooling bath was removed after 20 minutes and the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was partitioned between an ice-water mixture (100 ml) and tert-butyl methyl ether (100 ml). The organic layer was collected. The aqueous layer was extracted with two 100-ml portions of tert-butyl methyl ether. The combined organic layers were washed with one 30-ml portion of 2M aqueous sodium hydroxide solution, one 30-ml portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness to give the crude title compound (0.145 g). The batches were combined and purified by flash-chromatography with n-heptane/ethyl acetate as eluent to give the title compound (0.16 g, 51%) as colorless oil. MS m/e: 252 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:35]6[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]6)=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 8.5 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol), Piperidine (102 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 232 (46.2 mg, yield: 8.5%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.10 (d, J=4.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.78-7.77 (m, 2H), 7.50-7.40 (m, 1H), 7.18 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.64 (s, 4H), 3.16 (s, 2H), 1.63-1.57 (m, 4H) ESI-MS: m/z=543 [M+H+]