Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](I)[CH:8]=2)[CH:3]=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].[C:23](=[O:26])([O-])[O-:24].[K+].[K+].CN(C)C=O>O>[C:13]([C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[S:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:23]([OH:24])=[O:26])[CH:8]=2)[CH:3]=1)([OH:22])=[O:21]
Reactant: Ic1ccc2cc(I)ccc2c1
Reactant: O=C(O)c1ccccc1S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1Sc1ccc2cc(Sc3ccccc3C(=O)O)ccc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of 2,6-diiodonaphthalene (38.0 grams, 0.10 mole), thiosalicyclic acid (30.8 grams, 0.20 mole), potassium carbonate (27.3 grams, 0.20 mole) and N,N-dimethylformamide (200 ml) was heated and stirred at 130°-135° C. for 8 hours. An isolated sample showed mostly starting material and half-reacted product. More N,N-dimethylformamide (50.0 ml) was added and the reaction mixture was heated for an additional 30 hours at about 150° C. The reaction mixture was drowned into water (500 ml) and the "milky" mixture was filtered using Celite filter aid to remove the unreacted 2,6-diiodonaphthalene. The filtrate was acidified with concentrated HCl to precipitate the product which was collected by filtration and washed with water. The wet cake was ground using a mortar and pestle and then reslurried in methanol. After collecting the solid by filtration, washing with methanol and drying in air, forty grams of crude product were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>>[ClH:12].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: Cl
Product: O=S(=O)(Cl)c1cccnc1

Procedure:
1 g (6.3 mmol) of pyridine-3-sulphonic acid and 1.4 g (6.7 mmol) of phosphorus pentachloride are stirred for 2 hours at 150° C. After cooling, excess phosphorus pentachloride is eliminated in vacuo. The crude product is further reacted immediately.
Reaction SMILES: C(O[CH2:5][C:6]1[NH:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([CH3:16])[C:7]=1[C:17](=O)[CH3:18])(=O)C.[C:20]([C:25]1[CH:29]=[CH:28][NH:27][C:26]=1[CH3:30])([O:22][CH2:23][CH3:24])=[O:21].C(OCC)(=O)C>ClCCCl.ClCCl>[CH3:16][C:8]1[C:7]2[C:6](=[CH:5][C:29]3[C:25]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:26]([CH3:30])[NH:27][C:28]=3[C:17]=2[CH3:18])[NH:10][C:9]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: CCOC(=O)c1[nH]c(COC(C)=O)c(C(C)=O)c1C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)c1[nH]c2cc3c(C(=O)OCC)c(C)[nH]c3c(C)c2c1C
Yield: 6.1 %

Procedure:
A solution of ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate (0.267 g, 1.0 mmol) and 3-carbethoxy-2-methylpyrrole (0.153 g, 1.0 mmol) in 1,2-dichloroethane (10 cm3) was heated at reflux and stirred with Montmorillonite clay (1 g) for 18 h. After filtration from clay and washing well with 1,2-dichloroethane, evaporation of the combined filtrates under reduced pressure gave an oil. This oil was submitted to flash chromatography on silica eluting with (0-20%) ethyl acetate in dichloromethane to give the starting 3-carbethoxy-2-methylpyrrole (0.045 g, 29.4%) and diethyl 1,5-dihydro-3,4,6-trimethylpyrrolo[2,3-f]indole-2,7-dicarboxylate as a colourless solid (0.021 g, 6.14%) m.p. 269° C. (decomp); δH ([2H6]-DMSO)11.34 (1H, s, 5-NH), 11.00 (1H, s, 1-NH), 7.80 (1H, s, 8-H), 4.33 (2H, q, 7-OCH2CH3), 4.26 (2H, q, 2-OCH2CH3), 2.85 (6H, s, 3-CH3 and 4-CH3), 2.69 (3H, s, 6-CH3), 1.39 (3H, t, 7-OCH2CH3), and 1.37 (3H, t, 2-OCH2CH3); saturation of the singlet 8-H at δ 7.80 enhanced the signal due to 1-NH at δ 11.00 (2.3%); m/z (%) 342 (75,M+), 296 (100), 268 (6), 223 (7) and 195 (5) (Found: M+ 342.1580. C19H22N2O4 requires M, 342.1579; λ max EtOH/nm (log ε max.dm3 mol−1 cm−1 378 (3.56), 365 sh (353), 329 (3.83), 3.04 (3.99) and 259 (3.74). Further elution gave diethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]indole-2,5-dicarboxylate as a colourless solid (0.048 g, 14%) m.p. 216-216.5° C. (Found: C, 66.82; H, 6.68; N, 8.17. C19H22N2O4 requires C, 66.65; H, 6.48, N, 8.18%); δ ([2H6]-DMSO) 11.30 (1H, s, 7-NH), 10.91 (1H, s, 1N-H), 7.12 (1H, s, 8-11), 4.35 (2H, q, 5-OCH2CH3), 4.28 (2H, q, 2-OCH2CH3), 2.90 (3H, s, 4-CH3), 2.87 (3H, s, 3-CH3, 2.54 (3H, s, 6-CH3), 1.36 (3H, t, 5-OCH2CH3) and 1.34 (3H, t, 2-OCH2CH3); saturation of the 8-H proton at δ 7.12 enhanced the signals due to 7-NH at δ 11.30 (2.4%) and 1-NH at δ 10.91 (1.8%); m/z (%) 342 (64, M+), 296 (100), 250(5), and 194(9); λ max (EtOH)/nm (log ε max/dm3 mol−1 cm−1) 340 (4.10), 327.5 (4.53) and 270 (4.46), and the starting 5-acetoxymethyl-4-acetylpyrrole (0.029 g, 10.9%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH:9]1([C:12]2[C:13]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:34]=[CH:33][C:32](I)=[CH:31][C:30]=4[F:36])=[O:28])[CH2:23][CH2:22]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:11][CH2:10]1>>[CH:9]1([C:12]2[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([C:29]4[CH:34]=[CH:33][C:32]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:31][C:30]=4[F:36])=[O:28])[CH2:25][CH2:26]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:10][CH2:11]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: O=C(c1ccc(I)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: C[C@H]1CN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)c(F)c2)S(=O)(=O)C1
Yield: 32.8 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (235 mg) described in Preparation Example 4 and [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (570 mg) described in Preparation Example 164 and by the reaction and treatment in the same manner as in Example 1, the title compound (190 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:14]3[C:19]([C:20]=2C)=[CH:18][C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:43][CH2:44][CH2:45][CH2:46]I>C(#N)C>[Cl:1][C:2]1[C:10]([O:11][CH2:46][CH2:45][CH2:44][Cl:43])=[CH:9][C:8]([C:12]2[N:13]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:36]
Reactant: Cc1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)n(C(=O)OC(C)(C)C)c2ccc(CN3CCCCC3)cc12
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 84.5 %

Procedure:
In a similar manner to Step 1 of Example 433, 4-chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)methylindol-2-yl]isoindolinone (100 mg, 0.202 mmol) was suspended in acetonitrile (5.0 mL), and the suspension was treated with cesium carbonate (98.7 mg, 0.303 mmol) and 1-chloro-3-iodopropane (0.026 mL, 0.242 mmol), followed by purification by flash column chromatography (chloroform/methanol=19/1, 4/1) to obtain 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (97.7 mg, yield 84%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]4)=[CH:26][N:27]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: Nc1ccc(N2CCNC(=O)C2)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNC(=O)C4)cn3)nc2n1C1CCCC1
Yield: 23 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.34 mmol) and 4-(6-amino-pyridin-3-yl)-piperazin-2-one (111 mg, 0.578 mmol) gave 7-cyclopentyl-2-[5-(3-oxo-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (35 mg, 35%). MS(ESI) m/z 449.2 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].Br[CH2:23][C:24]1[O:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1.[Cl:33]CC1C=NC(OC)=NC=1>>[Cl:33][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:1]([CH2:23][C:24]1[O:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1)[C:2](=[O:21])[C:3]12[C:10]2=[CH:20][C:19]3[CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[C:11]2[O:12][CH2:13]1
Reactant: COc1ncc(CCl)cn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(Cl)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using T-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 5-(chloromethyl)-2-methoxypyrimidine, 7′-chloro-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one was obtained (30%) as a colorless solid: mp 210-211° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ7.34-7.31 (m, 1H), 7.21-7.16 (m, 2H), 7.10-7.05 (m, 1H), 6.67-6.65 (m, 1H), 6.49 (s, 1H), 6.43 (s, 1H), 5.34 (s, 2H), 4.85 (d, J=9.6 Hz, 1H), 4.74 (d, J=9.6 Hz, 1H), 4.57-4.48 (m, 2H), 2.94 (t, J=3.0 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.4, 161.2, 160.4, 154.1, 139.4, 138.9, 137.2, 135.4, 130.5, 124.6, 122.8, 120.6, 120.1, 119.9, 118.7, 117.1, 114.3, 114.2, 108.7, 92.4, 79.8, 72.0, 56.6, 28.1.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH3:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH:18]=[N+:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CC1C=C(C=CC=1)C=O.N1CCCCC1>>[N:19]1([CH:18]([C:17]2[CH:16]=[C:15]([CH3:14])[CH:27]=[CH:26][CH:25]=2)[C:5]2[N:1]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH2:12])[CH:2]=[CH:3][CH:4]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cccc(C=[N+]2CCCCC2)c1
Reactant: Nc1ccccc1-n1cccc1
Agent: Cc1cccc(C=O)c1
Agent: [Cl-]
Solvent: C1CCNCC1
Product: Cc1cccc(C(c2cccn2-c2ccccc2N)N2CCCCC2)c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-phenylamine and 1-(3-methyl-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 3 from 3-methylbenzaldehyde and piperidine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[NH:17][C:18](=[O:19])[N:12]4[C:13]=3[C:8]=2[CH2:9][CH2:10][CH:11]4[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[N:17]([CH3:27])[C:18](=[O:19])[N:12]4[C:13]=3[C:8]=2[CH2:9][CH2:10][CH:11]4[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1CCC3c1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1noc(C)c1-c1ccc2c3c1CCC(c1ccccc1)n3c(=O)n2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution of 7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (10.7 g, 0.031 mmol) in N,N-dimethylformamide (0.50 mL) was treated with cesium carbonate (20.2 g, 0.062 mmol) followed by methyl iodide (2.9 μL, 46.5 μmol) and stirred at room temperature for 16 h. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (8.2 mg, 74%) as a racemic mixture. 1H NMR (400 MHz, CDCl3) δ 7.35-7.20 (m, 3H), 7.03 (d, J=6.9 Hz, 2H), 6.99-6.93 (m, 1H), 6.93-6.84 (m, 1H), 5.53 (s, 1H), 3.49 (s, 3H), 2.48-2.11 (m, 7H), 2.09-1.84 (m, 3H); LCMS calculated for C22H22N3O2 (M+H)+: m/z=360.2. found: 360.1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18])C.C([O-])([O-])=O.[K+:28].[K+]>CO>[K+:28].[F:1][C:2]([F:12])([F:11])[C:3](=[N:18][C@H:17]([C:16]([O-:23])=[O:15])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)C[C@H](N=C(c1ccccc1)C(F)(F)F)C(=O)[O-]
Temperature: 50 °C

Procedure:
2,2,2-Trifluoroacetophenone (4.24 g, 24.3 mmol) was added to a mixture of L-leucine ethyl ester (3.52 g, 22.1 mmol) and K2CO3 (2.90 g, 20.9 mmol) in MeOH (50 mL). The mixture was warmed to 50° C. for 18 h. The mixture was cooled to 20–25° C., filtered and concentrated. The residue was suspended in TBME (100 ml) and filtered to give the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]([Cl:29])=[CH:17][C:16]=1[C:30](=[O:33])[CH2:31]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>CN(C)C=O>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([CH2:31][C:30]([C:16]2[CH:17]=[C:18]([Cl:29])[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][C:15]=2[O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:33])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(CBr)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
Cesium carbonate (2.95 g, 9 mmol) was added in three portions to a stirred solution of 1-(2,4-Bis-benzyloxy-5-chloro-phenyl)-2-bromo-ethanone (4.4 g, 9 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.74 g, 9 mmol) in dimethylformamide (20 ml). The suspension was stirred for 2 h then partitioned between water (200 ml) and ethyl acetate (3×50 ml). The combined organic extracts were washed with water (100 ml), dried over magnesium sulphate and concentrated to give 4-[2-(2,4-Bis-benzyloxy-5-chloro-phenyl)-2-oxo-ethyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil (4 g)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1ccccc1
Reactant: CC(O)c1ccc(Br)cn1
Product: CC(O)c1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, brown solid, MS: m/e=224.2 (M+H+), can be prepared in accordance with the general method of example 31, step 1 from rac-1-(5-bromopyridin-2-yl)ethanol and phenylacetylene.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:24])[C:22]=2[OH:23])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13].C(N(CC)CC)C.[CH3:35][CH2:36][S:37][C:38](Cl)=[O:39].C(OCC)(=O)C>C1COCC1>[CH3:27][O:26][CH:3]([O:2][CH3:1])[CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:24])[C:22]=2[O:23][C:38]([S:37][CH2:36][CH3:35])=[O:39])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COC(COc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C)OC
Reactant: CCSC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(OCC(OC)OC)c2C)cnn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 5-hydroxy-1-methylpyrazol-4-yl 3-(2,2-dimethoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone obtained in the above step (3) was dissolved in anhydrous THF (10 mL), and triethylamine (250 mg) and 96% S-ethyl chlorothiolformate (200 mg) were added, followed by stirring for 1 hour at room temperature. Ethyl acetate (200 mL) was added to the obtained reaction mixture, and the mixture was washed twice with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the desired product (150 mg).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([S:10][C:11]1[CH:16]=[CH:15][CH:14]=CC=1)C=C.[CH2:17]([Al](CC)CC)C>O>[C:3]1([S:10][CH2:11][CH:16]([CH3:17])[CH2:15][CH3:14])[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCC
Reactant: C=CCSc1ccccc1
Reactant: CC[Al](CC)CC
Solvent: O
Product: CCC(C)CSc1ccccc1
Reaction time: 72 h
Yield: 80.5 %

Procedure:
Hexane (1 ml) was added to (cyclopentadienyl)(1-[(1'S,2'S,5'R)-2'-isopropyl-5'-methylcyclohexyl]-4,5,6,7-tetrahydroindenyl)zirconium dichloride complex (20 mg, 4 mol %, prepared as in Example 1) in a 25 ml schlenk flask containing a stirring bar. Allylphenylthioether (150 mg, 1 mmol) was added and the flask evacuated and refilled 3 times with argon. Triethylaluminum (6 ml, 1.0 M in hexane, 6 mmol, 6 eq) was added dropwise. The solution turned yellow and was left for 72 hours. Water (10 ml) was added dropwise, the organics were extracted with diethylether (3×5 ml) and the combined extracts were dried over magnesium sulphate. The solvents were removed under reduced pressure and Kugelrohr distillation yielded the title compound as a clear liquid (145 mg, 0.85 mmnol, 80.5% yield, e.e 57% (FS-Hydrodex-B, 110° C.)).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].CN(C=O)C.C(N(C(C)C)CC)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40]([OH:42])=[O:41])=[CH:34]2>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35]([C:40]([OH:42])=[O:41])=[CH:34]4)=[O:14])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Reactant: Nc1ccc2[nH]c(C(=O)O)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cc(NC(=O)c3cc4cc([N+](=O)[O-])ccc4o3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of 93.2 mg (0.45 mmol) 5-nitrobenzofuran-2-carboxylic acid (128) in 6 mL DMF 209.0 mg (0.45 mmol) PyBroP and 157 μL (0.9 mmol) diisopropylethylamine was added and the clear solution was stirred for 10 minutes at room temperature. The activated acid was transferred to resin 127 which was agitated for 5 hrs. The resin was drained, washed twice with DMF. The analytical sample showed no complete reaction and therefore the activation/coupling reaction was repeated once again the same way using fresh reagents. The resin was drained, washed five times with DMF to give 129 which was used immediately as described in Example 117.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].Cl.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2.C(N(C(C)C)CC)(C)C>CS(C)=O.[Cl-].[Na+].O>[CH:16]12[N:19]([C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[F:1])[CH:12]([CH2:18][CH2:17]1)[CH2:13][CH2:14][CH2:15]2
Reactant: C1CC2CCC(C1)N2
Reactant: N#Cc1ccc(F)c(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2C3CCCC2CC3)c(F)c1
Temperature: 120 °C

Procedure:
3,4-Difluorobenzonitrile (1.75 g; 25.1 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (2.1 g; 13.8 mmol), and diisopropylethylamine (3.2 g; 25.1 mmol), were combined in DMSO (30 mL) and heated at 120° C. overnight. The mixture was allowed to cool to ambient temperature, poured into brine (75 mL), and extracted with diethyl ether (2×50 mL). The organics were combined, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered through a pad of silica gel (ethyl acetate as eluent) to provide the title compound. 1H NMR (DMSO-d6) δ 7.69 (dd, 1H), 7.42 (dd, 1H), 7.15 (t, 1H), 4.41 (s, 2H), 1.98 (m, 2H), 1.62-1.86 (m, 5H), 1.41 (m, 3H); MS (ESI) m/z 231, (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C.C(O)(=O)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][C:33]=1[S:40]([N:43]=[CH:44][N:45]([CH3:47])[CH3:46])(=[O:42])=[O:41].C([BH3-])#N.[Na+]>CO>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:19][C@H:16]2[CH2:15][CH2:14][C@@H:13]([O:12][C:11]3[C:2]([Cl:1])=[C:3]4[C:8](=[CH:9][CH:10]=3)[CH:7]=[N:6][CH:5]=[CH:4]4)[CH2:18][CH2:17]2)=[CH:34][C:33]=1[S:40]([N:43]=[CH:44][N:45]([CH3:46])[CH3:47])(=[O:42])=[O:41]
Reactant: N[C@H]1CC[C@@H](Oc2ccc3cnccc3c2Cl)CC1
Reactant: CN(C)C=NS(=O)(=O)c1cc(C=O)ccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)C=NS(=O)(=O)c1cc(CN[C@H]2CC[C@@H](Oc3ccc4cnccc4c3Cl)CC2)ccc1Cl
Reaction time: 0.5 h
Yield: 90 %

Procedure:
34 mg (0.11 mmol) cis-4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexylamine (13) were dissolved in 5 ml MeOH and 22 mg (0.22 mmol) triethylamine were added. After the reaction was stirred 30 min, 65 mg (1.1 mmol) acetic acid, 60 mg (0.22 mmol) 2-chloro-N-dimethylaminomethylene-5-formyl-benzenesulfonamide (73) and freshly dried molecular sieves were added and the mixture was stirred for 30 minutes at room temperature. A solution of 20.5 mg (0.33 mmol) sodium cyanoborohydride in 1 ml methanol was added and the mixture was allowed to stand at room temperature overnight. The solvent was removed i. vac. The residue was dissolved in dichloromethane, washed with 1N NaOH and brine, dried over MgSO4 and evaporated. 53 mg of the title compound were isolated as crude product and used without further purification. Rt=0.87 min (Method #4). Detected mass: 535.2/537.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([CH:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: c1ccc(C2CCCN2)cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Cl)cnc1N1CCCC1c1ccccc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of Methyl 2,5-dichloronicotinate (120 mg, 0.58 mmol,) in isopropanol (10 ml), 2-phenylpyrrolidine (86 mg, 0.58 mmol, available from Matrix Scientific #018619) and N,N-Diisopropylethylamine (90 mg, 0.70 mmol) were added. The mixture was heated under reflux overnight. After cooling to room temperature, the mixture was evaporated and the residue was dissolved in ethyl acetate (10 ml), washed with water (10 ml) and brine (10 ml), dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 20:1 to afford the title compound (D72) (167 mg) as colorless oil.