Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](O)[CH:9]=[CH2:10].COC(OC)(C)C>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[CH2:10]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])[CH:9]=[CH2:8]
Reactant: O=C1CCCCC1
Reactant: C=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: C=CCC1CCCCC1=O
Yield: 71.7 %

Procedure:
A solution of cyclohexanone (98.1 g, 1 mol), allyl alcohol (127.8 g, 2.2 mol), dimethoxypropane (114.6 g, 1.1 mol), and PTSA.H2O (0.1 g, 0.5 mmol) in toluene (0.51) was heated at reflux in a flask equipped with a microdistillation column (30×2.5 cm, filled with Raschig rings). After collecting the fractions distilling at 25-60° C. and 60-110° C., the residue (120 g) was distilled using a 10 cm-Vigreux-column (0.07-0.06 mbar, head temperature: 57° C.) giving 2-allylcyclohexanone (99.1 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of the product of Example 26a (553 mg, 1.557 mmol) in anhydrous DMF (15 mL) was treated with 4-mercaptophenol (196 mg, 1.557 mmol) and cesium carbonate (1.015 g, 3.114 mmol) at room temperature, then heated at 100° under a nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature and the solvent concentrated under vacuum giving the title compound. The residue was taken up in H2O (30 mL) and the pH adjusted to 3 with 1N aqueous HCl. The aqueous was then extracted with ethyl acetate, and the combined organic extracts washed with brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum giving the title compound. The residue was triturated with methylene chloride and purified by silica gel flash chromatography with a gradient of 6% to 30% ethyl acetate/methylene chloride to afford the title product as a dark yellow solid (517 mg, 1.16 mmol, 75%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:10])[C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][NH:10][C:9]1[C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)[CH3:18]
Reactant: Nc1cccc2c1CCO2
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNc1cccc2c1CCO2)OCC
Temperature: 100 °C

Procedure:
A mixture of 2,3-dihydro-benzofuran-4-ylamine (preparation. J. Hetereocyclic Chem., 18, 1333 (1980)) (4.34 g), potassium carbonate (8.87 g) and bromo acetaldehyde diethyl acetal (9.7 ml) in dry DMF (60 ml) was heated to 100° C. for 2 days under. The mixture was cooled and was partitioned between water and ethyl acetate. The dried extracts were evaporated and the residue chromatographed on silica gel (250 g). Elution with ethyl acetate:cyclohexane 1:4 gave the title compound as a pale yellow oil (4.95 g).
Reaction SMILES: [NH2:1][OH:2].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:4]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)C>[OH:2][NH:1][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][C:3]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NO
Reactant: CCOC(=O)/C=C\C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Hydroxylamine Free base (50% aqueous solution, 45.0 g, 0.68 mol) was added dropwise to a solution of diethyl maleate (100.0 g, 0.56 mol) in ethanol (100 mL) in a 3-neck flask blanketed with nitrogen. The reaction temperature was maintained below 55° C. with an ice bath. The mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to give crude diethyl N-hydroxyaspartate (103 g, 89% yield). The product was analyzed by nuclear magnetic resonance spectroscopy (NMR) and shown to be at least 95% pure. NMR (acetone-d6) 1.20 (m, 6H), 2.59 (dd, J 6.8, 16.1 Hz, 1H), 2.76 (dd, J 6.8, 16.1 Hz, 1H), 3.89 (t, J 6.8 Hz, 1H), and 4.11 (m, 4H).
Reaction SMILES: ClC(Cl)(Cl)CC(=N)O[CH:6]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([N:26]([CH3:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)[N:15]=2)=[CH:12][CH:13]=1)[CH3:7].[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40].C(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:33][N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[N:22]=[C:23]([NH2:25])[N:24]=[C:19]([C:16]2[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH:6]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])[CH3:7])=[CH:9][N:10]=3)[O:18][N:17]=2)[N:20]=1
Reactant: OCC(F)(F)F
Reactant: CC(OC(=N)CC(Cl)(Cl)Cl)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(OCC(F)(F)F)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 5 %

Procedure:
1-[6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-3-yl]ethyl 2,2,2-trichloroethanecarboximidate (Intermediate 139, 0.497 g, 0.93 mmol) was suspended in DCE (8 mL). 2,2,2-Trifluoroethanol (0.669 mL, 9.29 mmol) and tetrafluoroboric acid diethyl ether complex (0.025 mL, 0.19 mmol) were added and the mixture was stirred at room temperature for 7 h. LCMS showed incomplete conversion, so further tetrafluoroboric acid diethyl ether complex (0.125 mL, 0.93 mmol) was added and the mixture stirred at room temperature for 21 h. DCM (100 mL) and saturated aq. sodium bicarbonate (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate and concentrated under vacuum to yield a brown solid, which was purified by FCC using a gradient of 0-5% MeOH in DCM. The crude product was then purified by preparative HPLC, Method D, to afford an off-white solid. This was further purified by FCC using a gradient of 0-3% MeOH in DCM to afford the title compound as an off-white solid (0.022 g, 5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][S:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:22])[C:19]([CH3:21])([CH3:20])[O:18][BH:17][O:16]1.C(N(CC)CC)C.O>O1CCOCC1.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>[CH3:14][C:15]1([CH3:22])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][S:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:16]1
Reactant: CC1(C)OBOC1(C)C
Reactant: Brc1ccc(N2CCSCC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(N3CCSCC3)cc2)OC1(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To a mixture of 4-(4-bromophenyl)thiomorpholine (0.40 g), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.40 g) and triethylamine (0.65 mL) in 1,4-dioxane (15 mL) was added dichlorobis(triphenylphosphine)palladium(II) (0.054 g) under argon atmosphere. The reaction mixture was stirred at 100° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.40 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>CC(O)=O>[Cl:1][C:2]1[C:3]([N:12]2[CH:15]=[CH:19][CH:18]=[CH:17]2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])c(N)cc1Cl
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(-n2cccc2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-chloro-2-nitro-1,4-phenylenediamine [CAS-no. 26196-45-2] (4.69 g, 25 mmol), 2,5-dimethoxytetrahydrofuran (4.2 mL, 32.5 mmol) in HOAc (150 mL) at 95° C. for 2 h according to the general procedure F. Obtained as a red solid (4.10 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]=[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([OH:18])[CH:16]=2)[N:11]=[CH:10][NH:9]1.CS(O[C@H:26]1[CH2:31][CH2:30][C@H:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[C:34](=[O:39])[CH2:33]2)[CH2:28][CH2:27]1)(=O)=O.O>CN1CCCC1=O>[O:7]=[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([O:18][C@H:26]3[CH2:27][CH2:28][C@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[C:34](=[O:39])[CH2:33]4)[CH2:30][CH2:31]3)[CH:16]=2)[N:11]=[CH:10][NH:9]1
Reactant: CN1CCN([C@H]2CC[C@H](OS(C)(=O)=O)CC2)CC1=O
Reactant: COc1cc2nc[nH]c(=O)c2cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2nc[nH]c(=O)c2cc1O[C@H]1CC[C@H](N2CCN(C)C(=O)C2)CC1
Reaction time: 20 h

Procedure:
2.4 g sodium carbonate are added to 2 g of 3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline (VII) in 16 ml N-methyl-2-pyrrolidinone at 130° C. Then six times 600 mg (in total: 2.4 g) (trans)-1-methanesulphonyloxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane (II) are added stepwise at 130° C. within 4 h and the mixture is kept at 130° C. for 20 h. After 10 days, 25 ml of water are added and the mixture is extracted with 25 ml isopropyl acetate, 50 ml of dichloromethane and 25 ml of dichloromethane. The organic phases are evaporated down and the residue is separated off by preparative HPLC. 500 mg of the product are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]2[C:18]([O:20][CH3:21])=[O:19])[CH:2]=1.[Cl-:22].[Li+].C(OCC)(=O)C>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:12][C@@H:11]([Cl:22])[CH2:10][C@H:9]2[C:18]([O:20][CH3:21])=[O:19])[CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1Cc1cccnc1
Reactant: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1Cc1cccnc1
Reaction time: 4.5 h
Yield: 88.4 %

Procedure:
In an atmosphere of nitrogen, (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-methylsulfonyloxypyrrolidine (84.65 g) was dissolved in polyethylene glycol-400 (400 ml) followed by addition of lithium chloride (40 g, 0.943 mol). The mixture was warmed to 85°-90° C. and stirred at that temperature for 4-5 hours. The reaction mixture was then cooled to -20°~-25° C. and ethyl acetate (800 ml)-water (400 ml) was added thereto for extraction. After phase separation, the aqueous layer was adjusted to pH 9-9.5 with 24% sodium hydroxide in water (pH prior to adjustment: 4.8) and extracted with ethyl acetate (400 ml) twice. The ethyl acetate layer was combined and washed with a saturated aqueous sodium chloride solution (200 ml). The ethyl acetate solution was then concentrated to dryness under reduced pressure to provide (2S,4S)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-chloropyrrolidine (60.6 g) as an oil.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27]>CC(C)=O>[CH2:26]([N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1)[CH3:27]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=[N+]([O-])O
Product: CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Reaction time: 2 h

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitrate salt (1.03 g/4 mmol) was suspended in acetone (10 mL). Potassium carbonate and iodoethane were added sequentially and the suspension was heated to reflux with vigorous stirring for 2 hours. The mixture was then filtered through a pad of celite (rinsing with acetone) and the filtrate concentrated onto silica gel. 3-Ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine was isolated by column chromatography on silica gel (eluting with 0→10% methanol/methylene chloride) as a yellow/orange oil (600 mg/72%). 1H NMR (400 MHz, CDCl3) δ 7.98 (m, 2H), 7.28 (m, 1H), 3.15 (s, 4H), 2.91 (s, 4H), 2.79 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)=[N+]=[N-].Cl.[NH2:12][N:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>C(O)C.C(O)C.O>[O:15]=[C:14]1[NH:16][C:17](=[O:18])[CH2:19][N:13]1[N:12]=[CH:9][C:7](=[O:8])[CH:6]=[CH:5][C:4]#[N:1]
Reactant: [N-]=[N+]=Nc1ccc(C=O)o1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#CC=CC(=O)C=NN1CC(=O)NC1=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
A solution of 5-azido-2-furaldehyde (240 mg, 1.75 millimole (mmole)) in 20 milliliters (ml) of ethanol was added dropwise over 10-20 minutes to a solution of 1-aminohydantoin hydrochloride (320 mg, 2.1 mmole) in 25 ml of ethanol:water (4:1) and the mixture was chilled in an ice bath. The reaction mixture turned into a yellow-orange suspension within thirty minutes and was gradually heated to about 60° C. to form a complete solution. The heating continued for another 24 hours after which time it was allowed to cool and evaporated to dryness. The dark residue was triturated with 4-5 portions (15 ml each) of acetonitrile to obtain a suspension which was then filtered through a filter paper. The filtrate was evaporated to dryness. The residue was dissolved in 3 ml of acetone and streaked on two preparative silica gel TLC plates (EM Science, Cat # 5717-7) and developed with ethyl acetate: petroleum ether (3:1). The fast moving major band (Rf around 0.51) detected under UV light was stripped, and the silica gel was ground to a fine powder and eluted with acetone. The acetone eluent was evaporated to give a pale yellow solid which showed a homogeneous single spot on TLC (137 mg, 0.67 mmole, 38% yield). Alternatively the crude reaction product can be purified by silica gel column chromatography and further recrystallized from 30% ethyl acetate/hexanes to give the pure desired product (mp 171-173° C.). Elemental analysis supported a molecular formula of C8H6N4O3. 0.15 EtOAc. The structure of compound 1 was established by 1H and 13C NMR analysis as shown in FIGS. 1-4. 1H NMR analysis of 1 revealed that the acrylonitrile moiety has a trans (E)-configuration (coupling constant J=16.5 Hz). MALDI-TOF mass spectral analysis confirmed structure 1 with the M+1 peak of 207.22
Reaction SMILES: [CH2:1]([CH:7]1[CH:10](CC(OC2CCCCO2)CCCCCCCCCCC)[O:9][C:8]1=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH+]1C=CC=CC=1.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41](S([O-])(=O)=O)=[CH:40][CH:39]=1.C([OH:51])C>>[OH:51][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:48][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:1][CH:7]1[CH2:10][O:9][C:8]1=[O:31]
Reactant: CCO
Reactant: CCCCCCCCCCCC(CC1OC(=O)C1CCCCCC)OC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCCCCCCCCCC(O)CC1COC1=O

Procedure:
(1B.a) 265 mg of an isomer mixture of 3-hexyl-4-[2-[(tetrahydro-2H-pyran-2-yl)oxy]tridecyl]-2-oxetanone are dissolved in 2.5 ml of ethanol and 13 mg of pyridinium-4-toluenesulphonate are added. The reaction mixture is heated to 55°-60° C. until the reaction has finished. The solvent is removed in vacuo and the residue is taken up in ether, whereby there separate crystals which are removed by filtration. The solvent is evaporated off in vacuo and the residue is chromatographed on silica gel. There is obtained rac-3-hexyl-4-(2-hydroxytridecyl-2-oxetanone (2R,3S,4S:2S, 3R,4R), MS: M+ (354), m.p. 44.5°-46° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.I[C:16]1[CH:30]=[CH:29][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23][CH2:22]2)=[CH:18][CH:17]=1>>[O:28]=[S:24]1(=[O:27])[CH2:25][CH2:26][N:21]([CH2:20][C:19]2[CH:29]=[CH:30][C:16]([NH:1][C:2]3[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:3]=3)=[CH:17][CH:18]=2)[CH2:22][CH2:23]1
Reactant: O=S1(=O)CCN(Cc2ccc(I)cc2)CC1
Reactant: N#Cc1cn(-c2ccccc2)nc1N
Product: N#Cc1cn(-c2ccccc2)nc1Nc1ccc(CN2CCS(=O)(=O)CC2)cc1

Procedure:
3-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}amino)-1-phenyl-1H-pyrazole-4-carbonitrile was prepared according to the general procedure in Example 11 Step 1 using 3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (100 mg, 0.543 mmol) and 4-(4-iodobenzyl)thiomorpholine 1,1-dioxide (191 mg, 0.543 mmol) as the starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].[CH3:16][C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1>>[CH3:22][C:20]1[O:21][C:17]([CH:16]=[C:10]2[CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]=3[C:11]2=[O:15])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: Cc1ccc(C=O)o1
Product: COC(=O)c1ccc2c(c1)CCC(=Cc1ccc(C)o1)C2=O

Procedure:
The title compound was prepared according to Method A3 from 5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396 mg, 1.9 mmol) and 5-methyl-2-furaldehyde (192 mg, 2.0 mmol). ES-MS m/z 297 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][CH2:17][CH2:18][CH:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([NH:23][CH:19]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH3:16])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)C=Cc1ccc(OC)c(OC)c1

Procedure:
Prepared in a similar manner as described in example 4 from 3-(3,4-dimethoxy-phenyl)-acrylic acid and 4-heptylamine. MS (M+H, 306.2).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:21]=[C:20]([C:22]2[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([Cl:28])=[N:26][CH:27]=2)[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:12][C:13]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][C:25]([Cl:28])=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:23]=3)[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[S:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Reactant: O=C(Cl)c1cccc(CCl)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3cccc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(hydroxymethyl)-2-pyridinecarboxylic acid (500 mg, 3.27 mmol) in chloroform (10 ml) and DMF (0.1 ml) was added thionyl chloride (1 ml, 13.70 mmol) and the mixture heated at 65° C. for 1 hr. Solvent was removed in vacuo and the residue was azeotroped with chloroform (5 ml) then dried on a high vacuum line for 30 mins to afford an orange oil (650 mg), presumed to be 6-(chloromethyl)-2-pyridinecarbonyl chloride. N-{5-[4-amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methanesulphonamide (600 mg, 1.255 mmol) was dissolved in DCM (5 ml) and pyridine (0.122 mL, 1.506 mmol) was added followed by 6-(chloromethyl)-2-pyridinecarbonyl chloride (281 mg, 1.255 mmol) in DCM (5 ml). The reaction was stirred at 0° C. for 1 hr. A further portion of 6-(chloromethyl)-2-pyridinecarbonyl chloride (281 mg, 1.255 mmol) was added and the mixture stirred at 0° C. for 30 mins. The crude mixture was partitioned between saturated aqueous sodium bicarbonate solution (10 ml) and DCM (10 ml). The organic layer was separated using a hydrophobic frit, washed with water (10 ml) and concentrated in vacuo to give an orange solid which was purified by column chromatography (80 g silica RediSep column) eluting with 0-10% MeOH/DCM over 20 column volumes. Separation was incomplete, so all fractions were combined and the solvent was removed in vacuo. The resultant orange solid was re-purified by column chromatography on silica (80 g silica RediSep column) eluting with 50-100% EtOAc/cyclohexane over 40 mins on the ISCO Companion. Fractions containing desired material were combined to afford the title compound as a pale yellow solid (141 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[NH:9][CH:8]=[CH:7][C:6]2=O.C1(C)C=CC=CC=1.S(Cl)([Cl:32])=O>CN(C=O)C>[ClH:32].[Cl:32][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCCCN1CCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Product: Cl
Yield: 100 %

Procedure:
A solution of 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-1,4-dihydroquinolin-4-one (950 mg, 3.1 mmol) in thionyl chloride (25 ml) containing DMF (10 drops) was heated at reflux for 1.5 hours. After cooling, toluene was added and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline hydrochloride (1.23 g, 100%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:14][C:15]1[C:20](Cl)=[CH:19][C:18]([NH2:22])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.C(O)(C(F)(F)F)=O.O>CN(C=O)C.O>[NH2:22][C:18]1[C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:15]([Cl:14])=[C:20]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:3]2[CH2:2][OH:1])[CH:19]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: OC[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCC[C@@H]2CO)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-Hydroxymethyl-pyrrolidine (202 mg, 2.0 mmol) followed by potassium carbonate (304 mg, 2.2 mmol) were added to a mixture of 4,5-dichloro-2-nitro-phenylamine (414 mg, 2.0 mmol) in DMF (10 mL) and stirred at rt overnight. The reaction mixture was diluted with water, acidified with TFA:H2O 1:1 and filtered. The filtercake was washed with DMF:H2O 1:1 and dried to give the sub-title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>CC(O)C>[BrH:12].[O:1]([CH2:8][CH2:9][CH2:10][NH:11][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCOc1ccccc1
Reactant: Oc1ccc(OCCBr)cc1
Solvent: CC(C)O
Product: Br
Product: Oc1ccc(OCCNCCCOc2ccccc2)cc1
Yield: 20.4 %

Procedure:
A solution of 3-phenoxy-1-propanamine (24.2 g, 160 mmol) in 100 mL of 2-propanol is heated to reflux and treated slowly with a solution of 4-(2-bromoethoxy)phenol (17.4 g, 80 mmol) in 150 mL of 2-propanol. The mixture is heated at reflux for 4 days, then cooled and partitioned between ethyl ether and aqueous sodium bicarbonate solution. The organic layer is evaporated and the residue recrystallized from ethanol to give 6.0 g (20%) of product, mp 204-205° C.