Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].C(OC(C)C)(C)C.[F:13][C:14]([F:35])([S:31](F)(=[O:33])=[O:32])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20]>>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][S:31]([C:14]([F:13])([F:35])[C:15]([F:29])([F:30])[C:16]([F:27])([F:28])[C:17]([F:25])([F:26])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])(=[O:33])=[O:32]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCCCN
Solvent: CC(C)OC(C)C
Product: NCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
111 g (1.5 moles) of 1,3-diaminopropane and 300 g of fully dehydrated isopropyl ether were weighed in an atmosphere of nitrogen into a 2-liter three-necked round-bottomed flask equipped with a cooling condenser and stirrer. With sufficient stirring, 237 g (0.59 mole) of perfluorohexyl sulfonyl fluoride was added dropwise at room temperature from a dropping funnel. The mixture was stirred at 50° C. for 3 hours, and then the isopropyl ether was removed under reduced pressure. The oily residue was dissolved in 200 ml of ethanol, and gradually poured into 5 liters of distilled water with stirring. The resulting crystals were aged. The supernatant liquid was removed by decantation, and 1 liter of 0.5 N aqueous sodium hydroxide solution was added to wash the crystals. Decantation was performed for three more times using 5 liters of distilled water each time. The crystals were collected by filtration, washed with distilled water and dried at 60° C. under reduced pressure. There was obtained 268 g of N-(3 -aminopropyl)perfluorohexyl sulfonamide having a sufficient purity for use in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[C:3]1[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH2:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]([Cl:15])=[C:3]1[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Nc1cccc2c1C1CCC2C1=C(Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)Nc2cccc3c2C2CCC3C2=C(Cl)Cl)c(C(F)F)n1
Temperature: 80 °C
Yield: 83.4 %

Procedure:
9-Dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (166 g, 35% xylene solution, 0.25 mol), triethylamine (28 g, 0.275 mol) and xylene (13 g) were charged in a reactor and the mixture was heated to 80° C. 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (182 g, 26% xylene solution, 0.25 mol) was added over 2 hours. After conversion, the product was extracted, concentrated and crystallized in a mixture of xylene/methycyclohexane. 83 g of pure product were isolated. (Purity: 97%, Yield: 82%) 1H-NMR (400 MHz, CDCl3): δ=8.12 (bs, 1H, NH); 8.05 (s, 1H, Pyr-H); 7.83-7.80 (d, 1H, Ar—H); 7.19-7.15 (t, 1H, Ar—H); 7.04 (d, 1H, Ar—H); 7.02-6.76 (t, 1H, CHF2); 4.1 (s, 1H, CH); 3.95-4.0 (bs, 4H, CH & CH3); 2.18-2.08 (m, 2H, CH2); 1.55-1.3 (2m, 2H, CH2).
Reaction SMILES: ClS(C1C=C(C=CC=1F)C(O)=O)(=O)=O.[CH:15]([NH2:18])([CH3:17])[CH3:16].[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30](NCC)(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]>>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30]([NH:18][CH:15]([CH3:17])[CH3:16])(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: CC(C)N
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Agent: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Product: CC(C)NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F

Procedure:
1.002 g (3.6 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 0.94 mL (10.9 mmol) isopropylamine following the general procedure in for 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOCCOC>[NH2:32][C:28]1[CH:27]=[C:26]([NH:33][C:2]2[CH:3]=[C:4]([N:13]([CH:23]3[CH2:25][CH2:24]3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: Nc1cccc(N)c1
Agent: [Cu]I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: COCCOCCOC
Product: COc1ccc(CN(c2cc(Nc3cccc(N)c3)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 125 °C
Yield: 9.2 %

Procedure:
A 1-dram vial was charged with 1-methoxy-2-(2-methoxyethoxy)ethane (1.5 mL) and purged for 10 min with argon. The vessel was then charged with 1G (0.100 g, 0.28 mmol), benzene-1,3-diamine (0.037 g, 0.34 mmol), cesium carbonate (0.368 g, 1.13 mmol), copper(I) iodide (0.027 g, 0.14 mmol), Xantphos (0.033 g, 0.057 mmol), and Pd2(dba)3 (0.026 g, 0.028 mmol) in one portion. The resulting suspension was heated to 125° C. overnight. The suspension was filtered through a medium-porosity frit, and the solid was washed with THF. The filtrate was diluted with EtOAc and water, and the layers were separated. The aqueous phase was extracted three times with EtOAc. The organics were then combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was dissolved in DMF and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm), 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min, monitoring at 220 nm. Rt=53.697 min. The appropriate fractions were concentrated and lyophilized to dryness, affording 3A (11 mg, 9% yield). HPLC: Rt=3.68 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=426.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]2=[O:17])[CH:6]=[CH:7][CH:8]=1.[NH2-].[Na+].N.[CH2:21](I)[CH3:22]>C1(C)C=CC=CC=1.O.O1CCCC1>[CH2:21]([C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17])[CH3:22]
Reactant: COc1cccc(C2CCCCN(C)C2=O)c1
Reactant: CCI
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC1(c2cccc(OC)c2)CCCCN(C)C1=O
Yield: 63 %

Procedure:
Hexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one (4.66 g) in dry toluene (25 ml) was added dropwise to a stirred suspension of sodium amide (1.0 g) in dry toluene (50 ml). The reaction mixture was heated to reflux, ammonia was evolved and the reaction mixture became red. After refluxing for 2 hours dry tetrahydrofuran (20 ml) was added, the mixture cooled and ethyl iodide (3.7 g) added. A white precipitate was formed and the red colour rapidly disappeared. The reaction mixture was heated under reflux for 2 hours, cooled and decomposed by the addition of water. The aqueous phase was separated and the organic layer washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated affording an oil which crystallised from diisopropyl ether to give the title compound (3.29 g), m.p. 62°-64° C.
Reaction SMILES: [C:1]([N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)[C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(OCCCN(C(C)=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N(CCCOc1ccc(C(=O)O)cc1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 27 h
Yield: 94.5 %

Procedure:
Methyl 4-[3-[N-acetyl-N-(4-chlorophenyl)amino]propoxy]benzoate (1.20 g) was dissolved in methanol (20 ml), and 1N aqueous sodium hydroxide solution (4.99 ml) was added thereto, the mixture was heated with stirring at 60° C. for 27 hours. The reaction mixture was cooled, and the mixture was adjusted to pH 4-5 by adding conc. hydrochloric acid. The mixture was concentrated under reduced pressure and thereto was added water. The precipitate was collected by filtration, and washed with water to give the desired product (1.09 g). mp. 169°-171° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[B:21](OC)([O:24]C)[O:22]C.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH:15]1([O:14][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[B:21]([OH:24])[OH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Brc1ccccc1COC1CCCCC1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1COC1CCCCC1
Reaction time: 2 h

Procedure:
31.2 ml of n-butyllithium (1.6 M) in solution in n-hexane are added dropwise at −70° C. to 13.45 g of 1-bromo-2-[(cyclohexyloxy)methyl]benzene, obtained in step 1.1, in solution in 150 ml of tetrahydrofuran. After 2 hours at −70° C., 10.2 ml of trimethyl borate are introduced dropwise and the temperature of the reaction medium is allowed to rise to −30° C. The medium is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate and the organic phase is dried with anhydrous sodium sulfate. After evaporation, 11.7 g of a yellow oil are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1)[CH3:29]>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:27][C@@H:28]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH3:29])=[O:13])=[CH:7][C:6]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)cc1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)c(F)c1)c1ccc(NS(C)(=O)=O)cc1
Yield: 37.1 %

Procedure:
(4-tert-Butyl-3-fluorophenoxy)acetic acid (135 mg, 0.60 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (102 mg, 0.63 mmol), triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]phenyl}methanesulfonamide hydrochloride (150 mg, 0.60 mmol) were mixed in the same procedure described in Example 2(b) to furnish 94 mg (37% yield) of the title compound as a white solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[NH2:21][N:22]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]1[CH3:33]>>[CH3:33][C:23]1[N:22]([NH:21][CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: Cc1nc2ccccc2c(=O)n1N
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CNn2c(C)nc3ccccc3c2=O)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 3-amino-2-methylquinazolin-4(3H)-one. m/e+ 410 for C25H24N5O [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.22 (t, J=1.1 Hz, 1H), 7.71 (m, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.06 (dd, J=1.1, 9.1 Hz, 1H), 5.86 (t, J=4.8 Hz, 2H), 4.53 (bs, 1H), 2.42 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3, δ) 161.838, 155.787, 147.287, 146.870, 144.648, 137.968, 134.753, 131.113, 129.377, 128.399, 128.361, 127.246, 126.736, 126.457, 122.711, 121.779, 120.763, 117.161, 114.044, 43.949, 21.906, 21.459, 18.646 ppm.
Reaction SMILES: O[C:2]1[C:3]([Cl:12])=[C:4]([Cl:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CCOC1C=CC(N)=CC=1.O=P(Cl)(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][C:2]1[C:3]([Cl:12])=[C:4]([Cl:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nn2ccnc2c(Cl)c1Cl
Agent: CCOc1ccc(N)cc1
Solvent: ClCCl
Product: Clc1nn2ccnc2c(Cl)c1Cl
Temperature: 120 °C
Yield: 37 %

Procedure:
6-Hydroxy-7,8-dichloroimidazo[1,2-b]pyridazine (0.1 g, 0.5 mmol) from 1c was added to POCl3 (0.4 mL, 1.4 M) in a 1 dram vial. The mixture was heated to 120° C. for 2 days. Upon cooling CH2Cl2 was added and the mixture was poured onto ice water. The layers were separated and the aqueous layer was extracted with CH2Cl2 (15 mL). The organic layers were combined and washed with H2O (5 mL), followed by brine (5 mL). The solution was dried over Na2SO4 and concentrated in vacuo to give 6,7,8-trichloroimidazo[1,2-b]pyridazine as a tan solid (0.04 g, 37%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3](=[O:20])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:9]([O:18]C)[CH:8]=1)=[O:6].C[S-].[Na+].O>CN(C=O)C>[F:22][C:2]([F:1])([F:21])[C:3](=[O:20])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:9]([OH:18])[CH:8]=1)=[O:6]
Reactant: COc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1cscn1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)c(O)c1
Temperature: 120 °C
Yield: 99.9 %

Procedure:
To a stirred solution of 4,4,4-trifluoro-1-[3-methoxy-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione (395 mg, 1.2 mmol) in DMF (6 ml) was added sodium thiomethoxide (420 mg, 6.0 mmol) and the mixture was heated at 120° C. for 3 hours. The mixture was cooled down to room temperature, and poured into water. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give title compound (378 mg, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[N:10]=[N:11][NH:12][N:7]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nn[nH]n2)cc1
Temperature: 125 °C

Procedure:
A mixture of 4-aminobenzonitrile (10 g, 84.6 mmol), sodium azide (16.5 g, 254 mmol) and ammonium chloride (13.6 g, 254 mmol) in DMF was heated at 125° C. for 16 hours. The cooled mixture was filtered and the filtrate was concentrated in vacuo. The residue was added water (200 mL) and diethyl ether (200 mL) which resulted in crystallisation. The mixture was filtered and the solid was dried in vacuo at 40° C. for 16 hours to afford 5-(4-aminophenyl)-2H-tetrazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C.C(Cl)Cl>[CH2:13]([O:12][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH3:14]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To 4-bromo-2-fluoro-1-nitrobenzene (8.2 g, 37.27 mmol) in 50 mL of ethanol was added 21% by weight sodium ethoxide (16.4 mL, 52.2 mmol). The mixture was stirred at 60° C. for 1 h. The EtOH was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (MgSO4), filtered, and rotovaped down to give the title compound of step A (9.14 g, 37.14 mmol, 99.7%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (d, J=8.61 Hz, 1H), 7.20 (d, J=1.83 Hz, 1H), 7.14 (dd, J=8.61, 1.83 Hz, 1H), 4.16 (q, J=7.02 Hz, 2H), 1.47 (t, J=6.96 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[Br:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[C:35]([F:40])[CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[NH:37][C:36]1[CH:38]=[CH:39][C:33]([Br:32])=[CH:34][C:35]=1[F:40])=[O:5])[CH3:2]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCOC(=O)c1sc2cnccc2c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc2cnccc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A degassed solution of 3-(nonafluorobutane-1-sulfonyloxy)-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester (678 mg, 1.33 mmol), 4bromo -2-fluoroaniline (329 mg, 1.73 mmol), Pd2 dba3 (61 mg, 0.07 mmol), Xantphos (78 mg, 0.14 mmol) and DBU (509 μl, 3.35 mmol) in toluene (3 ml) was subjected to mnicrowave irradiation at 150° C. for 10 minutes. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate (70 ml). The resultant solution was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo to give an orange oil. The oil was purified by flash chromatography (Si-SPE, pentane:diethyl ether, gradient 90:10 to 50:50) followed by crystallisation from ethyl acetate:pentane to provide the title compound as a white solid (353 mg, 67%). LCMS (method B): RT=4.08 min, M+H+=395/397.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:11]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18][CH:12]3[NH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1.[C:30]1([O:36][CH2:37][CH2:38]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:11]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18][CH:12]3[N:13]([CH2:38][CH2:37][O:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2Nc3cccc(-c4ccc(Cl)cc4Cl)c3C2CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2c3c(-c4ccc(Cl)cc4Cl)cccc3N(CCOc3ccccc3)C2CC1
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 10-(2,4-dichlorophenyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate (54 mg) in DMF (1.2 ml) was added KH (10 mg) and 2-bromoethyl phenyl ether (30 mg). The reaction mixture was stirred 24 h, poured into satd NaHCO3, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated. Purification via flash chromatography provided the title compound: 1H NMR (CDCl3) δ 1.63, 2.30-2.50, 2.92, 3.14, 3.42, 3.75, 4.26, 4.53, 6.84, 6.96, 7.20-7.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:7][C:8]=1[C:9]1(CO)[CH:17]([CH:18]=[CH2:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1>[Pd]>[CH2:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:8]1[CH:7]=[C:6]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[N:5]=[N:4][C:3]=1[O:2][CH3:1])[CH3:19]
Reactant: C=CC1c2ccccc2NC1(CO)c1cc(-c2ccncc2)nnc1OC
Agent: [Pd]
Product: CCc1c(-c2cc(-c3ccncc3)nnc2OC)[nH]c2ccccc12
Reaction time: 4 h

Procedure:
12 mg Palladium, 10% on charcole are added to a solution of 70 mg 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-3-vinyl-1H-indole methanol and the reaction mixture stirred under an hydrogen atmosphere for 4 hours. The catalyst is removed by filtration and the solvens by evaporation yielding the product which was used without further purification
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1>C(#N)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CC#N
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-chloro-2-methylbenzenesulfonyl chloride (0.75 g, 0.0033 mol) in 5 mL of acetonitrile was added to a solution of tert-butyl (3S)-piperidin-3-ylcarbamate (0.67 g, 0.0033 mol) in 5 mL of acetonitrile at 0° C. After stirring at rt for 1.5 h the reaction mixture was filtered and concentrated to afford the desired product, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[CH2:15]([O:17][C:18]([C:20]1[N:21]([CH3:27])[C:22](Br)=[N:23][C:24]=1[CH3:25])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[N:21]([CH3:27])[C:22]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:23][C:24]=1[CH3:25])=[O:19])[CH3:16]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: CCOC(=O)c1c(C)nc(C#Cc2c(-c3ccccc3)noc2C)n1C
Yield: 63 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 110 mg, 63%) which was obtained as a light yellow solid. MS: m/e=350.3 [M+H]+.
Reaction SMILES: [Na].C[O:3][C:4](=O)[CH2:5][C:6]1=[N:7][N:8]([CH3:25])[C:9](=[O:24])/[C:10]/1=[C:11](\[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)/[CH2:12][CH2:13][CH2:14][CH3:15].Cl>CC(O)C>[CH2:12]([C:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4](=[O:3])[CH:5]=[C:6]2[NH:7][N:8]([CH3:25])[C:9](=[O:24])[C:10]=12)[CH2:13][CH2:14][CH3:15]
Reactant: CCCC/C(NCc1ccccn1)=C1/C(=O)N(C)N=C1CC(=O)OC
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Product: CCCCc1c2c(=O)n(C)[nH]c2cc(=O)n1Cc1ccccn1
Yield: 80 %

Procedure:
An isopropanolic solution of i-PrONa, obtained by dissolving of sodium (0.082 g, 3.57 mmol, 1 equiv.) in i-PrOH (75 ml), was treated with methyl[(4Z)-1-methyl-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]pentylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VIII) (0.61 g, 3.57 mmol, 1 equiv.). The reaction mixture was refluxed for 1 h, then cooled and neutralized to pH 7 by addition of 0.59 ml of a 20% aqueous HCl solution. 50 ml of i-PrOH were removed in vacuo and 25 ml of H2O were added before placing the flask in the fridge overnight. The white precipitate formed was filtered off, washed with water (2×5 ml), then with cyclohexane and dried in vacuo. 0.88 g of pure product 4-butyl-2-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione was obtained. Yield 80%. 1HNMR (DMSO-d6, 400 MHz): 0.80 (3H, t, J=7.2 Hz); 1.29-1.35 (2H, m); 1.38-1.43 (2H, m); 3.19 (3H, s); 3.22-3.24 (2H, m); 5.49 (2H, s); 5.72 (1H, s); 7.42 (1H, d, J=8 Hz); 7.62 (1H, t, J=6.6 Hz); 8.12 (1H, t, J=8 Hz); 8.65 (1H, d, J=5.2 Hz). MS (ESI+): 313.4; MS (ESI−): 311.3.