Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1I.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])=[C:6]([O:10][CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:13]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1cccc(OC)c1I
Product: COC(=O)c1cccc(OC)c1-c1ccccc1OC

Procedure:
Using the procedure outlined in Step A of Example 18, 201.7 mg (0.69 mmol) of methyl-2-iodo-3-methoxy-benzoate and 125.9 mg (0.82 mmol) of 2-methoxy-phenylboronic acid gave after 27 hours of reflux a quantitative yield of the title substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11](Cl)[C@@H:10]1[OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2>O1CCCC1.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[O:20][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@@H]1O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H]2O[C@H]12

Procedure:
A solution of (±)-(1R,2R,3R)-3-tert-butoxycarbonylamino-1-chloro-1,2,3,4tetrahydro-2-naphthalenol (348 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (400 mg) in tetrahydrofuran (10 ml) was refluxed for 11/2 hours. The mixture was diluted with methylene chloride, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from cyclohexane (193 mg) to yield the title compound as a white solid, m.p. 118-119° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CCCCCCC>[CH2:11]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:11]([C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[C:6]=1[CH2:9][CH2:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: c1ccc2ccccc2c1
Reactant: C=CCCCCCCCC
Solvent: CCCCCCC
Product: CCCCCCCCCCc1ccc2ccccc2c1CCCCCCCCCC
Product: CCCCCCCCCCc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 40 %
Yield: 57.3 %

Procedure:
A solution of naphthalene (16.3 g, 0.127 mole) in 25 ml of heptane was heated to 80° C. in the presence of 3 g of the catalyst. 1-decene, 14.9 g (0.106 mole), was added quickly. The reaction was stirred at 80° C. for 8 hours. The catalyst was removed by filtration and the excess naphthalene removed by rotary evaporation. The product was fractionated to give 11.5 g (40% yield) of decylnaphthalene, and 12.4 g (57.3% yield) of didecylnaphthalene. The didecylnaphthalene has KV: 9.9 cS@100° C.; 97 cS@40° C.; VI 87.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=2)([CH3:13])[CH2:11][O:10][S:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[OH2:25]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=2)([CH3:13])[CH2:11][O:10][S:9]1(=[O:25])=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)n1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)n2)COS1(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(6-bromo-pyridin-2-yl)-4-methyl-2-oxo-2lambda*4*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (8.83 g, 23.4 mmol) in acetonitrile (60 ml) and H2O (30.0 ml) was added RuCl3 hydrate (0.971 g, 4.68 mmol) and NaIO4 (10.01 g, 46.8 mmol). The reaction mixture was stirred at 0° C. for 2 h. H2O and DCM were added, the phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in DCM and filtered through silica gel, the filtrate was evaporated and the residue was triturated with TBME (10 ml) and n-hexane (100 ml). The resulting precipitate was filtered and washed with n-hexane to yield the title compound as a colourless crystalline solid. HPLC RtH4=1.16 min; ESIMS: 393, 395 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 7.63-7.59 (m, 1H), 7.47-7.42 (m, 2H), 4.73 (d, 1H), 4.47 (d, 1H), 2.00 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[C:29]([C:31]1([NH:37][C:38]([CH:40]([NH2:48])[CH2:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:39])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)#[N:30]>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:48][CH:40]([C:38](=[O:39])[NH:37][C:31]2([C:29]#[N:30])[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: N#CC1(NC(=O)C(N)CC2CCCCC2)CCOCC1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(C(=O)NC(CC2CCCCC2)C(=O)NC2(C#N)CCOCC2)cc1
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
4-Acetamidobenzoic acid (353 mg, 1.98 mmol), EDC (378 mg, 1.98 mmol), and HOBT (268 mg, 1.98 mmol) were combined in 15 mL of DMF and stirred for 20 min. Solid [1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amine hydrochloride (625 mg, 1.98 mmol) was added. The reaction was stirred for 16 hours. The volatiles were removed with a pump and the resulting residue was triturated, with rapid stirring, with 250 mL of saturated aqueous sodium bicarbonate. The resulting solid was collected by filtration and washed with 250 mL of water. The solid was dried in vacuo to give the title compound (250 mg); MS, m/z 441=M+1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CCOc1cc2ncc(C#N)c(NCc3ccc(Cl)c(Cl)c3)c2cc1OCC

Procedure:
In the manner of Example 61 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3,4-dichlorobenzylamine gave the title compound as a tan solid, mp 163-165° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.[CH3:23][C:24]1([CH3:33])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26](=O)[CH2:25]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[C:26]2[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29][C:24]([CH3:33])([CH3:23])[CH2:25]2)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCOCCO)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCCOCCO)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a stirred suspension of Zn (0.59 g, 9.00 mmol) in THF (10 mL) was added TiCl4 (0.50 mL, 4.50 mmol) dropwise. The mixture was refluxed under nitrogen for 2.5 h. After cooling to room temperature, a solution of 61 (0.34 g, 1.12 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.53 g, 3.37 mmol) in THF (15 mL) was added and the reaction mixture refluxed for an additional 2.5 h. Cooled to room temperature, the reaction was quenched with 10% K2CO3 (20 mL). The quenched reaction mixture was filtered through a pad of Celite and the pad washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel, the layers were separated, and the aqueous phase was extracted with EtOAc (50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give a pale yellow oil. The residue was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 55% EtOAc:hexanes to give 62 as a white solid (0.36 g, 75%). mp 122-124° C. 1H NMR (400 MHz, CD3OD): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.28 (s, 2H), 1.96 (s, 2H), 1.98 (s, 2H), 3.60-3.65 (m, 2H), 3.65-3.70 (m, 2H), 3.80-3.85 (m, 2H), 4.05-4.15 (m, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H). LRMS (APCI): m/z 425 (M+H)+, 423 (M−H)−. Anal. Calcd for C27H36O4: C, 76.38; H, 8.55; Found: C, 76.17; H, 8.65.
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.[CH3:12][CH2:13][O:14]CC.[O:17]([C@H:25]1[CH2:32][C@H:28]2[O:29][CH2:30][CH2:31][C@@H:27]2[CH2:26]1)[Si](C(C)(C)C)(C)C>C(Cl)Cl>[O:29]1[CH2:30][CH2:31][C@H:27]2[CH2:26][C@H:25]([O:17][C:13](=[O:14])[CH3:12])[CH2:32][C@H:28]12
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CCO[C@@H]2C1
Reactant: CCOCC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@@H]2CCO[C@H]2C1
Yield: 58 %

Procedure:
To the bicyclic ether (228 mg, 1.065 mmol) and Et3SiH (370 mg, 3.196 mmol) in CH2Cl2 (5 mL) at room temperature, was added BF3.OEt2 (450 mg, 3.196 mmol) following the same reaction conditions as described in the synthesis of compound 3 to obtain compound 5 (140 mg, 58% three steps) as an oil. 1H NMR (CDCl3, 200 MHz): δ 5 (m, 1H), 4.5 (m, 1H), 3.95 (m, 1H), 3.74 (m, 1H), 2.7 (m, 1H), 2.1 (m, 3H), 2 (s, 3H), 1.5-1.9 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][CH2:13][OH:14])[N:8]=1)[CH3:6].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[C:31]([O:14][CH2:13][CH2:12][C:9]1[N:8]=[C:7]([CH:5]([CH3:6])[C:4]2[CH:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:2]([F:1])[CH:3]=2)[O:11][N:10]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCO)no1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To a solution of 1.56 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-(2-hydroxyethyl)-1,2,4-oxadiazole in 40 ml of dry THF were successively added dropwise 0.56 g of triethylamine and 0.43 g of acetyl chloride with ice-cooling. After stirring for 4 hours at room temperature, the reaction mixture was poured into ice-water and extracted with benzene. The organic phase was washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel using chloroform to give 1.57 g of 3-(2-acetoxyethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as a colorless oil, nD23 1.5564.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[CH3:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[CH:17]=[N+:18]([CH3:20])[CH3:19].COC1C=CC=CC=1C=O.CNC>>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:17]([N:18]([CH3:19])[CH3:20])[C:16]1[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=1[O:14][CH3:13])[CH3:2]
Reactant: COc1ccccc1C=[N+](C)C
Reactant: CCc1cccc2cc[nH]c12
Agent: CNC
Agent: COc1ccccc1C=O
Agent: [Cl-]
Product: CCc1cccc2c(C(c3ccccc3OC)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and (2-methoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-methoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[C:19]1([CH3:26])C(C)=CC=CC=1.[ClH:27].[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32][Cl:33])[CH3:29]>O>[ClH:33].[ClH:27].[CH2:28]([N:30]([CH2:19][CH3:26])[CH2:31][CH2:32][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:29][CH2:28][N:30]([CH2:34][CH3:35])[CH2:31][CH3:32])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1)[CH3:29]
Reactant: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Reactant: Cc1ccccc1C
Reactant: CCN(CC)CCCl
Agent: Cl
Solvent: O
Product: CCN(CC)CCOc1ccc2c(c1)C(=O)c1ccc(OCCN(CC)CC)cc1C2=O

Procedure:
A stirred suspension of 30 g. of the powdered diphenoxide, containing about 24 g. (0.075 mole) of the dipotassium salt of 2,6-dihydroxyanthraquinone, in 200 ml. of xylene was heated to reflux and a small amount of water collected in the Dean-Stark distilling receiver. A solution of 2-diethylaminoethyl chloride in 100 ml. of xylene, prepared as in Example 1 from 50 g. (0.29 mole) of 2-diethylaminoethyl chloride hydrochloride, was then added and the resulting mixture heated to reflux for about 24 hours. The reaction mixture was poured into water and worked up exactly as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH2:4][C:5](=[O:40])[CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:25]C2CCCCO2)[C:18]([CH3:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:32]C2CCCCO2)[CH2:12][C:11]1=[O:39].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:41])[CH2:4][C:5](=[O:40])[CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:25])[C:18]([CH3:23])([CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:32])[CH2:12][C:11]1=[O:39]
Reactant: CCCCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCC(=O)CC(=O)OC)OC1CCCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCC(=O)CC(=O)OC
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 42.3 %

Procedure:
A mixture of 42 mg of the tetrahydropyran-2-yloxy compound (prepared as described in Example 2), 0.4 ml of 65% v/v aqueous acetic acid, and 4 drops of tetrahydrofuran was stirred for 5 minutes at 80° C. The reaction solution was diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to obtain 12.6 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:33][CH3:34])=[CH:20][C:21]([CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:31][CH3:32])O)=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].II.[PH2](=O)O.C(OCC)(=O)C>C(O)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:33][CH3:34])=[CH:20][C:21]([CH2:23][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:31][CH3:32])=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(O)c3ccccc3SC)cc(OC)c21
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3SC)cc(OC)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 118.8 %

Procedure:
To a mixture of 797 mg (1.67 mmol) [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-(2-methylsulfanyl-phenyl)-methanol, 436 mg iodine in 13 ml acetic acid (100%), 0.88 ml of phosphinic acid (ca. 5 equiv.) is added at room temperature. The mixture is heated to 60° C. and stirred for 1 h. After that the reaction mixture is allowed to cool to room temperature and 100 ml ethyl acetate is added. The combined organic layers are washed with 4N NaOH-solution (4×), water (2×) and brine, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford 914 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#N.[CH2:10]([Mg]Br)[CH2:11][CH3:12].C(Br)CC.CC[O:21]CC>>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1](=[O:21])[CH2:10][CH2:11][CH3:12])[CH:8]=1
Reactant: Cc1ccnc(C#N)c1
Reactant: CCC[Mg]Br
Reactant: CCOCC
Solvent: CCCBr
Product: CCCC(=O)c1cc(C)ccn1
Temperature: 25 °C

Procedure:
A solution of 2-cyano-4-methylpyridine (526 mg, 4.45 mmol) in Et2O (10 mL) added over 10 min to a rapidly stirring solution of freshly prepared n-PrMgBr (from n-PrBr (0.40 mL, 4.45 mmol) and Mg (132 mg) in Et2O (10 mL). Once addition was completed, the reaction was heated to reflux in a warm water bath for 2 hours. The reaction was cooled to RT then cooled in ice, quenched with 1 mL H2O then 13 mL 5N H2SO4. The ether phase was separated. The aqueous phase was heated in warm water for 15 minutes, then cooled in ice and basified with sat. K2CO3. The solution was extracted with CHCl3 and dried over K2CO3. The solution was filtered and concentrated to afford 372 mg of 1-(4-methylpyridin-2-yl)butan-1-one as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 8.51 (d, J=4.80 Hz, 1H), 7.85 (s, 1H), 7.27 (s, 1H), 3.17 (t, J=7.45 Hz, 2H), 2.41 (s, 3H), 1.69-1.79 (m, J=7.43, 7.43, 7.43, 7.43, 7.43 Hz, 2H), 0.99 (t, J=7.45 Hz, 4H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[N:30]1([CH:36]2[CH2:41][CH2:40][N:39]([C:42]3[CH:43]=[C:44]([NH2:48])[CH:45]=[CH:46][CH:47]=3)[CH2:38][CH2:37]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:48][C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([N:39]4[CH2:40][CH2:41][CH:36]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)[CH2:37][CH2:38]4)[CH:43]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1cccc(N2CCC(N3CCOCC3)CC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCC(N5CCOCC5)CC4)c3)nn12
Yield: 13.7 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (85.0 mg, 0.000296 mol), N,N-Diisopropylethylamine (0.0773 mL, 0.000444 mol) and 3-(4-Morpholin-4-yl-piperidin-1-yl)-phenylamine (155 mg, 0.000592 mol) were dissolved in 2-Methoxyethanol (2.08 mL) and The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 19.65 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine as a lyophilized powder. (M+H)=485.25. 1H NMR (400 MHz, DMSO, d6) δ 9.22 (s, 1H), 8.95 (s, 1H), 7.71 (m, 1H), 7.50 (t, 1H, J=6.88 Hz), 7.32 (m, 1H), 7.21 (m, 1H), 7.09 (m, 3H), 6.90 (q, 2H, J=5.65 Hz), 6.53 (m, 1H), 4.02 (m, 2H), 3.76 (s, 3H), 3.68 (t, 2H, J=12.16 Hz), 3.56 (m, 2H), 3.48 (m, 2H), 3.21 (m, 1H), 3.10 (m, 2H), 2.53 (m, 2H), 2.04 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Br[CH2:7][C:8]([NH:10][C:11]1[C:28]([OH:29])=[C:27]2[C:14]([CH2:15][CH:16]3[C:25]([C:26]2=[O:30])=[C:24]([OH:31])[C:23]2([OH:32])[CH:18]([CH:19]([N:38]([CH3:40])[CH3:39])[C:20]([OH:37])=[C:21]([C:34]([NH2:36])=[O:35])[C:22]2=[O:33])[CH2:17]3)=[C:13]([N:41]([CH3:43])[CH3:42])[CH:12]=1)=[O:9]>CN1C(=O)N(C)CCC1.C(#N)C>[CH3:40][N:38]([CH3:39])[C@H:19]1[C@H:18]2[C@:23]([OH:32])([C:24]([OH:31])=[C:25]3[C@H:16]([CH2:17]2)[CH2:15][C:14]2[C:27](=[C:28]([OH:29])[C:11]([NH:10][C:8](=[O:9])[CH2:7][N:3]([O:4][CH3:5])[CH3:2])=[CH:12][C:13]=2[N:41]([CH3:42])[CH3:43])[C:26]3=[O:30])[C:22](=[O:33])[C:21]([C:34]([NH2:36])=[O:35])=[C:20]1[OH:37]
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Reactant: CNOC
Agent: Cl
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: CON(C)CC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2
Yield: 51.2 %

Procedure:
The compound of the example is prepared by the procedure of Example 1 using 10 g of N,O-dimethylhydroxylamine hydrochloride (neutralized by NaOH, extracted with methylene chloride), and 1.0 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 8 ml DMPU and 2.5 ml acetonitrile to give 0.495 g of the product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]=[C:12]=S)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:23][CH2:24][C@@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][C:12]3[O:33][C@:25]4([CH2:24][N:23]=3)[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]4)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N=C=S)n[nH]c2c1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1ccc2c(NC3=NC[C@@]4(CN5CCC4CC5)O3)n[nH]c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To 6-fluoro-3-isothiocyanato-1H-indazole (0.20 g, 1.04 mmol) in DMF (15 mL) was added triethylamine (0.43 mL, 3.11 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.26 g, 1.14 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and treated with N,N′-diisopropylcarbodiimide (0.48 mL, 3.11 mmol). The reaction was then heated to 70° C. for 2 hours. The reaction was cooled to ambient temperature and concentrated. The crude product was purified by column chromatography (85% chloroform, 14% methanol, 1% ammonium hydroxide) to afford (R)—N-(6-fluoro-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.22 g, 0.66 mmol, 64% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 12.16 (s, 1H), 8.00 (s, 1H), 7.59-7.67 (m, 1H), 7.09 (dd, J=9.77, 2.14 Hz, 1H), 6.81-6.88 (m, 1H), 3.81 (d, J=9.16 Hz, 1H), 3.56 (d, J=8.85 Hz, 1H), 3.00 (s, 2H), 2.78 (s, 2H), 2.67 (t, J=7.32 Hz, 2H), 2.01 (d, J=2.44 Hz, 1H), 1.92 (s, 1H), 1.59 (d, J=5.80 Hz, 2H), 1.46 (s, 1H). MS (LC/MS) R.T.=1.44; [M+H]+=316.16.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][S:21]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)c1ccccc1C=O
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CS(=O)(=O)c1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methylsulfonylbenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methylsulfonylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.