Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][S:27]([OH:30])(=[O:29])=[O:28].C(O)C.C([BH3-])#N.[Na+]>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][S:27]([OH:30])(=[O:29])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCS(=O)(=O)O
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCS(=O)(=O)O)ccc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of 6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.1662 g, 0.5354 mmol) and Taurine (0.06700 g, 0.5354 mmol) in anhydrous Ethanol (4.00 mL, 68.5 mmol) was refluxed for 2 hours. The mixture was cooled to room temperature and Sodium cyanoborohydride (0.04037 g, 0.6425 mmol) was added. The mixture was then refluxed overnight. The reaction mixture was cooled to room temperature and washed with Sat. aqueous citric acid (4 mL). The mixture was then concentrated to dryness under reduced pressure. The resulting solid was suspended in water and filtered. The residue was washed with water, air-dried and purified by prep HPLC to give the title compound. ESI-MS (M+H+): 420.34; 1H NMR (400 MHz, DMSO-d6) Shift 8.68 (br. s., 1H), 7.84 (br. s., 1H), 7.73-7.81 (m, 2H), 7.45 (dd, J=1.76, 8.53 Hz, 1H), 7.32-7.35 (m, 1H), 7.12 (dd, J=2.51, 8.78 Hz, 1H), 4.29-4.38 (m, 1H), 4.24 (br. s., 2H), 3.13 (d, J=13.80 Hz, 2H), 2.76 (d, J=13.55 Hz, 2H), 2.10-2.18 (m, 2H), 1.72-1.80 (m, 2H), 1.23-1.36 (m, 2H), 1.09-1.22 (m, 2H), 0.96-1.06 (m, 1H), 0.81 (s, 9H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].[C:29]([C:31]1[N:32]=[C:33]([C:44]([O-])=[O:45])[N:34]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=1)#[N:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:44]([C:33]3[N:34]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=[C:31]([C:29]#[N:30])[N:32]=3)=[O:45])=[C:16]([C:21]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCCC3)c2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.4 %

Procedure:
A solution of 108 mg (0.292 mmol) 4-(4-amino-3-cyclohept-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH2Cl2 was treated with 97.9 mg (0.321 mmol) 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), 204 mg (0.437 mmol) PyBrOP, and 152 μL (0.874 mmol) DIEA and stirred at RT for 17 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated NaHCO3 (1×15 mL) and water (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 50-gm column with 10-25% EtOAc-hexane afforded 160 mg (88%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C30H42N5O4Si, 563.3 (M−C4H9+2H), found 563.9.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].[C:8](OC)(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].Cl>CS(C)=O>[NH2:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8](=[O:16])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccccc1N
Reactant: CS(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)CC(=O)c1ccccc1N
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
Dimethylsulfone (120 g, 1.28 mol) was stirred in DMSO (350 mL). Sodium hydride (48 g of 60 wt % in mineral oil) was added in portions and the mixture heated to 60° C. Methyl anthranilate (48.3 g, 0.32 mol) was added dropwise over 3 hours while the temperature rose to 100° C. The mixture was poured into ice (500 mL) and concentrated HCl (100 mL) and the mixture stored at 4° C. overnight. The mixture was extracted with dichloromethane (3×400 mL), and the combined extracts were washed with saturated bicarbonate (3×30 mL), dried (MgSO4), and reduced to 800 mL volume. The solid that formed was removed by filtration. The filtrate was reduced to 80 mL volume. The resulting solid was collected and washed with a small volume of dichloromethane. The solid was recrystallized from chloroform to give 1-(2-aminophenyl)-2-(methylsulfonyl)ethanone (24 g).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[CH:29][C:30]([F:39])=[C:31]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[CH:28]=[CH:29][C:30]([F:39])=[C:31]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:32]=3)[CH2:25][CH2:26]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)ccc1F

Procedure:
Example 65 was prepared from diphenylacetyl chloride and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 8.33–8.18 (m, 1H), 7.49–7.10 (m, 12H), 7.10–6.93 (m, 1H), 6.90–6.76 (br, 1H), 4.87 (s, 1H), 3.44–3.28 (m, 2H), 3.06–2.89 (m, 2H), 2.56–2.40 (m, 3H), 2.40–2.31 (m, 2H), 2.13–1.93 m, 2H), 1.86–1.52 (m, 8H), 1.01 (t, 3H, J=7.6 Hz) ESMS m/e: 516.6 (M+H)+; Anal. Calc. For (HCl salt) C32H39ClFN3O2.0.25CHCl3.1.00H2O: C, 64.49; H, 6.93; N, 6.99. Found: C, 64.23; H, 7.21; N, 6.99.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)=[O:6].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].[Cl-]>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Sodium hydride (0.37 g. 60%, 9.3 mmol) was added to a solution of indazole-3-carboxylic acid methyl ester (1.5 g, 8.5 mmol) in dry THF (50 mL) at 0° C. Benzyl bromide (1.59 g, 9.3 mmol) was then added and the reaction mixture was warmed to 25° C. and stirred for 8 h The reaction mixture was poured onto saturated NaCl solution (100 mL) and extracted with 3×200 mL of diethyl ether. The combined extracts were dried (MgSO4) and concentrated under reduced pressure. The crude compound was purified by flash chromatography using cyclohexane/ethyl acetate (70:30) and recrystallised from cyclohexane/ethyl acetate to afford the title compound as a yellow solid (1.89 g, 84%). Mp 72-73° C. 1H NMR (300 MHz, CDCl3) ppm 4.07 (s, 3H), 5.72 (s, 2H), 7.22-7.40 (m, 8H), 8.24-8.27 (m, 1H). MS(EI) m/z 266 [M+]. Anal. Calcd. for C16H14N2O2: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.12; H, 5.15; N, 10.85.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12](=O)[C:13]([C:28]#[N:29])=[CH:14][N:15](CC3C=CC(OC)=C(OC)C=3)[CH:16]=2)[CH:8]=[CH:9][CH:10]=1.[Li+].[Cl-:32]>O=P(Cl)(Cl)Cl>[Cl:32][C:12]1[C:13]([C:28]#[N:29])=[CH:14][N:15]=[CH:16][C:11]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[CH:6]=1
Reactant: [Cl-]
Reactant: COc1ccc(Cn2cc(C#N)c(=O)c(-c3cccc(OCCCl)c3)c2)cc1OC
Agent: [Li+]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cncc(-c2cccc(OCCCl)c2)c1Cl
Yield: 75.2 %

Procedure:
A solution of 5-[3-(2-chloroethoxy)-phenyl]-1-(3,4-dimethoxybenzyl)-4-oxo-1,4-dihydro-pyridine-3-carbonitrile (2.5 g, 5.9 mmol) and LiCl (2.3 g, 53 mmol) in 22 mL of POCl3 was heated at reflux for 2.5 h. The excess POCl3 was removed by concentrating in vacuo. The residue was dissolved in 100 mL CH2Cl2 and washed with ice-cold 3 N NaOH. The organic layer was separated, dried over anhydrous MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with 30% EtOAc in hexanes to yield 1.3 g (75% yield) of 4-chloro-5-[3-(2-chloroethoxy)phenyl]nicotinonitrile as an off-white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([CH3:16])[NH:11]1.[I-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([CH3:16])[N:11]1[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: COC(=O)CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COC(=O)CCCN1[C@H](C)CCC[C@@H]1C

Procedure:
A mixture of 273 g. of methyl 4-chlorobutyrate, 460 g. of cis-2,6-dimethylpiperidine, 10 g. of sodium iodide and 300 ml. of xylene is stirred and heated at reflux for 44 hours, then cooled and filtered. The filter cake is washed with xylene and the combined filtrate and washings are evaporated at reduced pressure to give cis-2,6-dimethyl-1-piperidinebutyric acid, methyl ester which is purified by distillation; b.p. 79°-81° C./0.5 mm.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[CH:6][C:5]=1[C:9]([O:11]C)=[O:10].Cl.C(O)(=O)C.O>CC(C)=O>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[CH:6][C:5]=1[C:9]([OH:11])=[O:10]
Reactant: COCc1oncc1C(=O)OC
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COCc1oncc1C(=O)O

Procedure:
Methyl 5-(methoxymethyl)isoxazole-4-carboxylate (Preparation 42, 1.8 g, 11 mmol) was stirred in a 1:1:1 mixture of concentrated hydrochloric acid (2 ml), acetic acid (2 ml) and water (2 ml) at reflux for 6 hours. Acetone (6 ml) was added and the mixture concentrated in vacuo. The solid residue was triturated with ethyl acetate and the filtrate concentrated in vacuo to afford the title compound as an off white solid (1.4 g, 85% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][NH:12][S:11](=[O:15])(=[O:14])[NH:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:16].[C:17]1(B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1>>[C:17]1([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:13][NH:12][S:11](=[O:15])(=[O:14])[NH:10][CH2:9]3)[CH:5]=[CH:4][C:3]=2[NH2:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Nc1ccc(C2CNS(=O)(=O)NC2)cc1Br
Product: Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Yield: 65 %

Procedure:
2-Bromo-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenylamine (as prepared in the previous step, 46.9 mg, 0.153 mmol) was reacted with cyclohexane-1-enyl boronic acid (24.1 mg, 0.191 mmol) according to the Suzuki coupling procedure of Example 4, step (e) and purified on silica (20-100% EtOAc-hexane) to afford the title compound (30.7 mg, 65%): Mass spectrum (ESI, m/z): Calcd. for C15H21N3O2S, 308.1 (M+H). found 308.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O[C:22]1[CH:31]=[CH:30][C:25]([O:26][CH:27]([OH:29])[CH3:28])=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([O:18][C:22]3[CH:31]=[CH:30][C:25]([O:26][CH:27]([OH:29])[CH3:28])=[CH:24][CH:23]=3)=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(O)Oc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(O)Oc1ccc(OC(=O)c2ccc(N=Nc3ccc([N+](=O)[O-])cc3)cc2)cc1
Yield: 76.1 %

Procedure:
A solution of 0.35 g of 4-(4-nitrophenylazo)benzoic acid, 0.2 g of (4-hydroxyphenoxy)ethanol and 0.04 g of 4-dimethylaminopyridine is reacted with 0.4 g of N,N'-dicyclohexyldicarbodiimide and 50 ml of dichloromethane in an analogous manner to Example 1 to give 0.4 g of (4-[4-(4-nitrophenylazo)benzoyloxy]phenoxy)ethanol.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1(CBr)CC1.N1C=CC=CC=1SC1SC(N)=NC=1>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[CH:6]=[CH:7]1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: BrCC1CC1
Agent: Nc1ncc(Sc2ccccn2)s1
Product: c1ccc2[nH]ccc2c1

Procedure:
6-fluoroindole, R5X=cyclopropyl-methylbromide; NH2A=5-(pyridin-2-ylsulfanyl)-thiazole-2-ylamine
Reaction SMILES: C([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>CCO.[OH-].[OH-].[Pd+2]>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[CH3:19][C:16]1([OH:18])[CH2:17][NH:14][CH2:15]1
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CNC1
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydryl-3-methylazetidin-3-ol (0.46 g, 1.82 mmol) in EtOH (15 mL) was added TFA (0.14 mL, 1.82 mmol) and Pd(OH)2/C (0.127 g, 0.182 mmol). The reaction was subjected to hydrogenation (50 psi) on a Parr shaker at ambient temperature overnight. The reaction mixture was filtered, concentrated and triturated with Et2O. The fine white solid was filtered to yield the product as a TFA salt.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[O:18])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN(C)CCCl
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN(C)CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Yield: 74.2 %

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (300 mg, 1.13 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (196 mg, 1.36 mmol), and cesium carbonate (1.11 g, 3.39 mmol) were reacted in accordance with the method of First Step of Example 3 to obtain 282 mg of the heading compound as a colorless powdery crystal (yield 74%).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(#N)C>[N:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: BrCCCCCCN1CCCCC1
Agent: [Li]CCCC
Solvent: CC#N
Product: O=C1Nc2ccccc2N(CCCCCCN2CCCCC2)c2ccccc21
Yield: 46 %

Procedure:
Prepared analogously to Example 6 from 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, n-butyl-lithium and 1-bromo-6-(1-piperidinyl)-hexane in a yield of 46% of theory. Colourless crystals, m.p. 124°-125° C. (from acetonitrile using activated charcoal).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(NC(C)C)(C)C.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1.[Na+].[I-]>CN1C(=O)CCC1.O>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19])=[CH:32][CH:31]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)CCCCCCCCCCCCCCC(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC(C)NC(C)C
Product: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)O)cc1
Temperature: 80 °C

Procedure:
Hexadecandioic acid (2 g, 7 mmol) was dissolved in dry NMP (25 mL). Diisopropylamin (1.2 mL, 7 mmol) and 4-methoxybenzyl chloride (0.95 mL, 7 mmol) was added, followed by NaI (0.52 g, 3.5 mmol). The mixture was heated to 80° C. for 1 hour, poured into water (100 mL) and filtered. The precipate was washed with dichloromethane (150 mL), the dichoromethane phase was dried (Na2SO4) and solvent removed in vacuo to yield the crude product, which was recrystallized several times from heptane to yield hexadecanedioic acid mono-(4-methoxy-benzyl)ester.
Reaction SMILES: ClC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[I:11].[Cl:30]C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I.ICl.FC1(F)C(F)(F)C1(F)F>>[Cl:30][C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[I:11]
Reactant: FC(F)(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: FC(F)(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: ClI
Agent: FC1(F)C(F)(F)C1(F)F
Product: FC(F)(Cl)C(F)(F)C(F)(F)I

Procedure:
As for a compound in which n is 9 or 11 in formula (22), 1-chloro-9-iodoperfluorononane (22-4) or 1-chloro-11-iodoperfluoroundecane (22-5) can be obtained by allowing iodine monochloride to react with commercially available perfluorocyclopropane (53) at a high temperature to obtain 1-chloro-3-iodoperfluoropropane (54), and then allowing 1-chloro-3-iodoperfluoropropane (54) to react with tetrafluoroethylene (51) under high temperature and pressurized conditions.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:43])[CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:34](=[O:43])/[CH:35]=[CH:36]/[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)/C=C/c3ccccc3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 30 mg, 0.074 mmol) and triethylamine (70 mg, 0.69 mmol) in dichloromethane (6 ml) was added cinnamoyl chloride (18 mg, 148 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain title compound. 1H NMR (CDCl3, 300 MHz): δ 9.921 (s, 1H), 8.204-8.257(d, 1H ,J=15.9 Hz), 8.071-8.123 (d, 1H,J=15.6 Hz), 7.983-8.013 (d, 1H J=9 Hz), 7.806-7.834 (d, 2H, J=8.4 Hz), 7.63-7.68 (m, 3H), 7.569-7.597 (d, 2H,J=8.4 Hz), 7.396-7.412 (m, 3H), 7.059-7.066 (d, 1H, J=2.1 Hz), 1.858 (s, 6H); MS: m/z 539 (M+).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[C:21]([N:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.6 %

Procedure:
Commercially available ethyl nipecotate (1.48 ml; 9.53 mmol) was dissolved in dichloromethane (20 ml), and diisopropylethylamine (1.82 ml; 10.45 mmol) was added. Benzoyl chloride (1.1 ml; 9.53 mmol) was then added slowly to control any rise in reaction temperature. After addition was complete the mixture was allowed to stir at ambient temperature for approximately 1-4 hours. The mixture was then diluted with fresh dichloromethane and washed with 1 N HCl. The dichloromethane solution was dried with anhydrous potassium carbonate and evaporated at ambient temperature under reduced pressure. The crude material was purified by high-vacuum distillation at approximately 200° C./0.1 torr giving ethyl 1-benzoyl-3-piperidinecarboxylate (2.38 g) as a colorless oil. (The temperatures given for distillations in these examples are oven temperatures and represent approximations. Similarly, the vacuum levels given for distillations are also approximates.) MS m/z (positive ion) 545 (dimer+; 25), 284 (M+Na+; 90), 262 (MH+; 100), 216 (25).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[C:30](Cl)(=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:30](=[O:39])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.28 ml triethylamine and 0.18 ml of 4-anisoyl chloride are mixed together then the reaction medium is agitated at ambient temperature for 30 minutes. Then 2 ml of water is added, followed by extracting with methylene chloride, drying and evaporating the solvents. Chromatography on silica is carried out (eluent methylene chloride/methanol/ammonium hydroxide 85/15/1.5 then CH2Cl2/CH3CN 8/2 then methylene chloride/methanol/ammonium hydroxide 85/15/1.5). 275 mg of expected product is collected.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:23][C:24]1[C:32]2[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=3)=[N:30][C:29]([CH3:40])=[N:28][C:27]=2[S:26][C:25]=1[C:41](O)=[S:42].CCN(C(C)C)C(C)C.[C:53]([NH2:57])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[C:53]([NH:57][C:41]([C:25]1[S:26][C:27]2[N:28]=[C:29]([CH3:40])[N:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=3)[C:32]=2[C:24]=1[NH2:23])=[S:42])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)N
Reactant: Cc1nc(-c2cccc(N)c2)c2c(N)c(C(O)=S)sc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cccc(N)c2)c2c(N)c(C(=S)NC(C)(C)C)sc2n1
Reaction time: 3 h

Procedure:
TBTU (16.1 g) was added to a solution of 5-amino-4-(3-aminophenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylic acid (example 1(f), 14.0 g), DIPEA (17.4 ml) and tert-butylamine (7.3 g) in DCM/DMF (1/1, v/v, 250 ml). After 3 h at room temperature, the mixture was diluted with DCM (50 ml), washed with sat. aq. NaHCO3 (3×100 ml), 0.1 N aq. HCl (100 ml) and water (100 ml). The organic layer was concentrated under reduced pressure. The crude product was purified by crystallisation from warm abs.