Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[C:5]1([CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][NH3+:30])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:31][C:32]([F:39])([F:38])[C:33](OCC)=[O:34]>CO>[C:5]1([CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][NH:30][C:33](=[O:34])[C:32]([F:39])([F:38])[F:31])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: [NH3+]CCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: CC(=O)[O-]
Solvent: CO
Product: O=C(NCCOCCOCCOCCOCCOCCOCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 800 mg of 19-phenyl-3,6,9,12,15,18-hexaoxanonadecylammonium acetate in 5 ml of MeOH was admixed with 75 μl of TEA and 609 μl of ethyl trifluoroacetate, and stirred at RT for 17 h. Solvents and excess reagents were removed, and the residue was filtered on a silica gel column (EE). Yield: 672 mg of colourless oil.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: BrCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 849.9 %

Procedure:
Dihydropyran (5.20 g, 6.11 mmol) was added to a stirring 0° C. solution of 7-bromoheptane-1-ol (2) (11.0 g, 56.7 mmol) and a catalytic amount of PTSA in CH2Cl2. After stirring at rt for 12 h, the reaction mixture was diluted with CH2Cl2 (200 mL), washed with water (100 mL×2), brine (100 mL×3), dried over anhydrous sodium sulphate, and evaporated. The residue was purified by silica gel column chromatography using a gradient of 10-20% ethyl acetate/hexane as eluent to give 2-(7-bromoheptyloxy)tetrahydro-2H-pyran (3) (14.50 g, 92%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.55; 1H NMR (400 MHz, CDCl3) δ 4.58-4.56 (m, 1H), 3.84-3.88 (m, 1H), 3.68-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.43 (m, 3H), 1.80-1.81 (m, 2H), 1.30-1.62 (m, 14H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: C[C@H](CO)NS(=O)(=O)c1ccccc1Br
Product: C[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C18H19N5O3S, 385.12; m/z found, 386.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 2H), 8.66-8.56 (m, 1H), 8.19 (dd, J=8.0, 1.4, 1H), 7.95 (dd, J=8.2, 2.3, 1H), 7.83 (dd, J=8.2, 0.9, 1H), 7.72 (m, 1H), 7.64 (m, 1H), 7.43 (dd, J=7.5, 1.4, 1H), 3.43-3.16 (m, 4H), 1.03 (d, J=6.6, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)O.C1C=CC(OP(OC2C=CC=CC=2)([N:28]=[N+:29]=[N-:30])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[N:11][CH:10]=1)[CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)=[N+:29]=[N-:30]
Reactant: OC(CC1OCCO1)c1ccc(C(F)(F)F)nc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC(CC1OCCO1)c1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(1,3-dioxolan-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol (18.54 g, 0.070 mol) and diphenylphosphonic azide (36 mL, 0.17 mol) in toluene (40 mL) was cooled to 0° C. and neat 1,8-diazabicyclo[5.4.0]undec-7-ene (25 mL, 0.17 mol) was added. The reaction mixture was stirred at 0° C. for 2 hr and then at 20° C. overnight. The mixture was washed with water and 5% HCl. The aqueous phase was extracted with CH2Cl2. The combined orangic layers were concentrated in vacuo and the residue was purified by silica gel column (0-100% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](/[CH:8]=[CH:9]/[CH2:10][O:11][N:12]=[C:13]([C:44]1[N:45]=[C:46]([NH:49]C=O)[S:47][CH:48]=1)[C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH:24]=[CH2:25])[CH2:22][S:23][C@H:18]12)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+].C(OC(C)C)(C)C>C(OCC)(=O)C.O1CCCC1.CO>[C:1]([O:5][C:6](/[CH:8]=[CH:9]/[CH2:10][O:11][N:12]=[C:13]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)[C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])=[C:21]([CH:24]=[CH2:25])[CH2:22][S:23][C@H:18]12)=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC/C=C/C(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC/C=C/C(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.6 %

Procedure:
A mixture of benzhydryl 7-[2-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.7 g), conc. hydrochloric acid (1.34 g), methanol (30 ml) and tetrahydrofuran (10 ml) was stirred at ambient temperature for 2.5 hours. To the reaction mixture was added ethyl acetate, followed by adjusting to pH 7.5 with a saturated aqueous sodium bicarbonate. The separated organic layer was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether to obtain benzhydryl 7-[2-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.50 g).
Reaction SMILES: [O-:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].C([S:12][CH:13]1[CH2:18][CH2:17][S+:16]([CH3:19])[CH2:15][CH2:14]1)(=O)C.[OH-].[Na+].Cl>>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[SH:12][CH:13]1[CH2:18][CH2:17][S+:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: CC(=O)SC1CC[S+](C)CC1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Product: C[S+]1CCC(S)CC1
Reaction time: 1 h

Procedure:
A cold (ice bath) aqueous solution (4 mL) of 4-acetylthio-1-methyl-tetrahydrothiopyraniumtriflate* (500 mg, 1.47 mmol) was treated with a 1M NaOH solution (2 mL, 2 mmol). The mixture was stirred for ca. 1 h. until all the starting material had disappeared on TLC (reversed phase silica gel). The pH of the strongly basic solution was brought to pH 7.5 with 10% HCl. This thiol was used as such for the next coupling reaction with the enol phosphate.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH:16][C:17](=[NH:19])[CH3:18])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[CH:23]([NH:26]N)([CH3:25])[CH3:24]>C(O)(=O)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:26]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:17]([CH3:18])[N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(C)NN
Reactant: CC(=N)NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1

Procedure:
9-Bromo-N-(1-iminoethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 29 was reacted with isopropylhydrazine hydrochloride 4 in acetic acid to give III.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[Br:30][C:31]1[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1>>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([NH:29][CH:17]2[CH2:18][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:20][N:15]([C:13]([CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:14])[CH2:16]2)=[O:38])=[N:35][CH:36]=1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: O=C(O)c1ccc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccc(Br)cn3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
139 mg (0.34 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 68 mg (0.34 mmol, 1.0 eq.) of 5-bromopyridine-2-carboxylic acid were reacted according to General Method 1. Yield: 75 mg (44% of theory)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]1=3)[CH2:30][CH2:29][O:28]4)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[N:33]1[CH:38]=[C:37]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:25][O:24][C:23]4[CH:26]=[C:27]5[C:31](=[CH:32][C:22]2=4)[CH2:30][CH2:29][O:28]5)[C:5](=[O:21])[N:6]3[CH2:11][C:12]2[O:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)[CH:36]=[N:35][CH:34]=1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(-c3cncnc3)c2C12COc1cc3c(cc12)CCO3
Yield: 28.3 %

Procedure:
A mixture of 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.11 g, 0.21 mmol), pyrimidine-5-boronic acid (0.04 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol), 2.00 M sodium carbonate (1.00 mL) and 1,2-dimethoxyethane (10.0 mL) was heated at reflux for 16 h under nitrogen. After the organic solvent was evaporated in vacuo, the black residue was extracted with ethyl acetate (3×35.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluting with ethyl acetate:hexane (35%) to afford the title compound (0.03 g, 26%): mp 263-266° C.; 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.14 (s, 2H), 7.39 (t, 1H), 7.10, (d, 1H), 6.87 (d, 1H), 6.76 (s, 1H), 6.51 (s, 1H), 6.46 (s, 1H), 6.07 (s, 1H), 5.03 (ABq, 2H), 4.62-4.48 (m, 21-1), 4.58 (ABq, 2H), 3.01 (t, 2H); 13C NMR (75 MHz, CDCl3) δ 177.3, 162.5, 161.0, 157.4, 155.9, 151.6, 142.2, 141.7, 132.8, 132.3, 131.3, 129.3, 125.7, 120.6, 120.2, 118.3, 117.0, 112.7, 109.7, 109.4, 93.5, 78.9, 72.5, 57.7, 37.1, 28.9; MS (ES+) m/z 506.5 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](Br)=[CH:11][C:10]=1[C:24]1[N:25]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[N:35]([CH3:39])[CH:34]=[CH:33]3)[C:26]([OH:29])=[N:27][N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH:45]=[CH2:46].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(N(C(C)C)CC)(C)C>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].CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:46]=[CH:45][C:44]2[CH:47]=[CH:48][C:49]([O:50][CH3:51])=[C:42]([O:41][CH3:40])[CH:43]=2)=[CH:11][C:10]=1[C:24]1[N:25]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[N:35]([CH3:39])[CH:34]=[CH:33]3)[C:26]([OH:29])=[N:27][N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccc2cc(-n3c(O)nnc3-c3cc(Br)c(OCc4ccccc4)cc3OCc3ccccc3)ccc21
Reactant: C=Cc1ccc(OC)c(OC)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C=Cc2cc(-c3nnc(O)n3-c3ccc4c(ccn4C)c3)c(OCc3ccccc3)cc2OCc2ccccc2)cc1OC
Temperature: 135 °C
Yield: 66 %

Procedure:
A flask was charged with 5-(2,4-Bis-benzyloxy-5-bromo-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-ol (290 mg; 0.50 mmol), 3,4-dimethoxystyrene (98 mg; 0.60 mmol), tris(dibenzylideneacetone)dipalladium(0) (11 mg; 0.025 eq.), tris-tert-butylphosphine (10 mg; 0.10 eq.), diisopropylethylamine (77 mg; 0.60 mmol), and dimethylformamide (2 mL). The reaction was heated at 135° C. overnight, and then cooled. The solution was diluted with ethyl acetate (40 mL) and washed with water (3×40 mL). The organic layer was dried with sodium sulfate, evaporated, and purified by column chromatography to give 5-{2,4-bis-benzyloxy-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-phenyl}-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-ol (220 mg; 0.33 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CCO.CO.[Pd]>[NH:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:4]1[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(-c2ncc[nH]2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1cc(-c2ncc[nH]2)ccc1N
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a mixture of 2-(3-methyl-4-nitrophenyl)-1H-imidazole (1.17 g, 5.76 mmol) and 10% Pd/C (0.8 g) in EtOH (5 mL) was added dropwise HCO2NH4 [3.63 g, 57.64 mmol., dissolving in MeOH (50 mL)]. After 1 h, TLC showed the reaction was complete. Filtration and the filtrate was evaporated under reduced pressure. The residue was dissolved in DCM (30 mL) and filtrated. The filtrate was concentrated to afford 4-(1H-imidazol-2-yl)-2-methylaniline as a yellow solid (1.0 g, 99%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][S:14][C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.[Br:22][C:23]1[CH:24]=[C:25]([CH:32]=[CH:33][CH:34]=1)[C:26](N(OC)C)=[O:27]>O1CCCC1.C(OCC)(=O)C.O>[Br:22][C:23]1[CH:24]=[C:25]([C:26](=[O:27])[CH2:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([S:14][CH3:13])[N:20]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: CSc1nccc(C)n1
Reactant: CON(C)C(=O)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1nccc(CC(=O)c2cccc(Br)c2)n1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
19.8 ml (140 mmol) diisopropylamine were dissolved in 250 ml dry tetrahydrofurane and cooled to −75° C. and 87.6 ml of a solution of n-butyllithium (1.6 M in hexane, 140 mmol) was added over a period of 20 minutes. After stirring for 15 minutes at −75° C. a solution of 13.1 g (93 mmol) 2-methylthio-4-methylpyrimidine in 80 ml dry tetrahydrofurane was added within 30 minutes at −75° C. and the mixture was stirred for additional 15 minutes. Then a solution of 25.1 g (103 mmol) B1 was added within 30 minutes at −75° C. The mixture was allowed to warm up to room temperature and was poured on 600 ml ethyl acetate/water (1:1). The aqueous layer was extracted with 50 ml ethyl acetate and the combined organic layers were dried over sodium sulphate. Removal of the solvent in vacuo yielded 23.3 g (77%) C1, m.p. 98-101° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.ClC(Cl)(Cl)C([N:40]=C=O)=O>ClCCl>[CH2:1]([O:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:40])[C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1OCc1ccccc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3ccccc3c2n1OCc1ccccc1
Temperature: 0 °C
Yield: 40.7 %

Procedure:
A solution of 1-(benzyloxy)-2-propyl-1H-imidazo[4,5-c]quinoline (2.6 g, 8.2 mmol) in dichloromethane (100 mL) was cooled to approximately 0° C., and 3-chloroperoxybenzoic acid (3.6 g of approximately 77% pure material, 16 mmol) was added over a period of several minutes. The reaction was stirred for ten minutes at 0° C., stirred for 90 minutes at room temperature, washed with saturated aqueous sodium bicarbonate (2×35 mL, containing 1 mL of 25% w/w aqueous sodium hydroxide), dried over potassium carbonate, and filtered. The resulting solution was cooled to 0° C., and trichloroacetyl isocyanate (1.22 mL, 10.3 mmol) was added with stirring. The reaction was stirred for 15 minutes at 0° C., stirred for 75 minutes at room temperature, and concentrated under reduced pressure. The residue was dissolved in methanol (60 mL), and sodium methoxide (6.3 mL of a 25% w/w solution in methanol, 29 mmol) was added with stirring. The mixture was stirred at room temperature overnight. A precipitate formed, and the reaction mixture was cooled to approximately 0° C. The precipitate was collected by filtration, recrystallized from methanol/water, and dried overnight in a vacuum oven at 70° C. to provide 1.11 g of 1-(benzyloxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, mp 164-166° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:31])([CH:28]([F:30])[F:29])[CH:11]=[CH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2].[H][H]>[Ni].C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:31])([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:15]=2)[CH:28]([F:30])[F:29])=[CH:8][CH:9]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOc1ccc(C(C)(C=CCc2ccc(F)c(Oc3ccccc3)c2)C(F)F)cc1
Agent: [Ni]
Solvent: CCO
Product: CCOc1ccc(C(C)(CCCc2ccc(F)c(Oc3ccccc3)c2)C(F)F)cc1

Procedure:
2.0 g (4.69 mmol) 4-(4-Ethoxyphenyl)-5,5-difluoro-1-(4-fluoro-3-phenoxyphenyl)-4-methyl-2-pentene was hydrogenated with hydrogen at atmospheric pressure with hydrogen in the presence of 0.2 g Raney nickel in 30 ml ethanol. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the solvent removed under reduced pressure. After chromatography on silica gel, using hexane/toluene, 1.8 g of the desired product remained i.e. 89.6% of theory.
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@H:4]([CH2:5][C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[CH2:8]2)[CH2:3][NH:2]1.Br[CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[C:19]1(=[O:28])[N:18]([CH2:17][CH2:16][CH2:15][N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][C:7]4[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=4[CH2:5]3)[CH2:1]2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: c1ccc2c(c1)C[C@@H]1CNC[C@H]1C2
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CC2Cc3ccccc3CC2C1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of trans-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (200 mg, 1.15 mmol), N-(3-bromopropyl)-phthalimide (309 mg, 1.15 mmol), potassium iodide (192 mg, 1.15 mmol), and potassium carbonate (320 mg, 2.31 mmol) in 10 mL of methylethyl ketone was heated at reflux for 8 hours. The mixture was cooled to room temperature, the solids were filtered, and the filtrate was concentrated in-vacuo. The residue was dry-loaded onto a 1×5 cm silica column, and eluted with ethyl acetate followed by 20% methanol/chloroform. Obtained 200 mg of an amber oil. Yield=48%. NMR (300 MHz, CDCl3) δ 7.87-7.83 (m, 2H), 7.76-7.70 (m, 2H), 7.15-7.07 (m, 4H), 3.80 (t, 2H, J=7 Hz), 3.22 (m, 2H), 3.01-2.87 (m, 4H), 2.76-2.56 (m, 4H), 2.11-1.96 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)[OH:5]
Reactant: O=Cc1ccccc1Br
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1ccccc1Br

Procedure:
To a solution of 2-bromobenzaldehyde (3.15 mL, 27.0 mmol) and THF (135 mL) at 0° C. was added (4-chlorophenyl)magnesium bromide solution (29.7 mL, 1M in THF, 29.7 mmol). The reaction was stirred at 0° C. for 30 min before addition of a saturated solution of ammonium chloride. The layers were separated and the aqueous extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage to afford (2-bromophenyl)(4-chlorophenyl)methanol. To a solution of DCM (100 mL) and oxalyl chloride (2.471 mL, 28.2 mmol) at −78° C. was added DMSO (3.34 mL, 47.0 mmol) and the reaction stirred at −78° C. for 15 min. After 15 min a solution of (2-bromophenyl)(4-chlorophenyl)methanol in DCM (25 mL) was added dropwise and stirred for 15 min at −78° C. before addition of Et3N (9.84 mL, 70.6 mmol). The cold bath was removed and the reaction was warmed to room temperature. To this solution was added water and the layers separated. The aqueous was extracted with DCM and the combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (2-bromophenyl)(4-chlorophenyl)methanone. LC/MS m/z 295 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([O:23]CC)=[O:22].C(O)C.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Yield: 83 %

Procedure:
3.8 g of ethyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate, 13 ml of ethanol and 1.0 g of sodium hydroxide are heated in 13 ml of water for 1 hour for boiling. The pH is reduced to 10 and the alcohol is distilled off in vacuo. The aqueous solution is shaken up with ether and purified with active charcoal. Acidification is carried out with dilute hydrochloric acid and with a yield of 83% 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained; F 179.5°-181°.
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([NH:12][C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@H:14]3[NH:22][CH3:23])=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:24].C(N(CC)CC)C.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([NH:12][C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@H:14]3[N:22]([C:34](=[O:35])[CH2:33][Cl:32])[CH3:23])=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:24]
Reactant: O=C(Cl)CCl
Reactant: CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CCl)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2,3-Dichloro-N-[(1R,2R)-1-(methylamino)-2,3-dihydro-1H-inden-2-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 11; 300 mg, 0.79 mmol) and triethylamine (167 μL, 1.2 mmol) was dissolved in DCM (5 mL), chloroacetyl chloride (73 μL, 0.9 mmol) added and the reaction stirred at ambient temperature for 2 hours. The volatiles were removed by evaporation under reduced pressure and EtOAc (15 mL) added. The mixture was washed with water (10 mL), brine (10 ml), dried (MgSO4) and the volatiles were removed by evaporation under reduced pressure to give the title compound (310 mg, 86%) as a pale brown foam.