Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:12]=1[O:13][C:14]1[C:15]([NH:24][S:25]([C:28]2[CH:37]=[CH:36][C:31]3[O:32][CH2:33][CH2:34][O:35][C:30]=3[CH:29]=2)(=[O:27])=[O:26])=[N:16][CH:17]=[N:18][C:19]=1[O:20][CH2:21][CH2:22][OH:23]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:12]=1[O:13][C:14]1[C:19]([O:20][CH2:21][CH2:22][O:23][C:8](=[O:9])[NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:18][CH:17]=[N:16][C:15]=1[NH:24][S:25]([C:28]1[CH:37]=[CH:36][C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[CH:29]=1)(=[O:27])=[O:26]
Reactant: O=C=Nc1cccnc1
Reactant: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc4c(c3)OCCO4)ncnc2OCCO)c1
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc4c(c3)OCCO4)ncnc2OCCOC(=O)Nc2cccnc2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
57 mg of 3-pyridyl isocyanate were added to 121.5 mg of N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-2,3-dihydro-1,4-benzodioxin-6-sulfonamide dissolved in 1 ml of dry toluene. The reaction mixture was stirred at 100° C. for 1 hour. Then, the solution was added to a silica gel column and it was eluted with EtOAc. There was obtained pyridin-3-ylcarbamic acid 2-[5-(2-chloro-5-methoxy -phenoxy]-6-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonylamino) -pyrimidin-4-yloxy]-ethyl ester, white powder, MS: m/e =630.4 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([CH2:36][C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: O=C(CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1)N1CCOCC1
Agent: Cl
Agent: [Li+]
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3CC(=O)N3CCOCC3)sc2CN1

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[[(morpholin-4-yl)carbonyl]methyl]piperazine hydrochloride
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:27])[C:8]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]2OS(C(F)(F)F)(=O)=O)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:27])[C:8]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]2[C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)c1c(C)cc2ccc(Br)cc2c1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (235 mg, 0.50 mmol) in PhCH3 (1.2 mL), EtOH (0.6 mL), H2O (0.6 mL) was added 4-chlorophenylboronic acid (86 mg, 0.55 mmol), K2CO3 (207 mg, 1.5 mmol), and PdCl2dppf (11 mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 2 h and was then diluted with H2O and EtOAc. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the titled compound and 37 mg of the bis-coupled product (ethyl 2-(1,7-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate). 1H-NMR: 400 MHz, (CDCl3) δ: 7.60-7.72 (m, 4H), 7.45 (m, 2H), 7.23 (m, 2H), 3.93 (q, J=7 Hz, 2H), 2.48 (s, 3H), 1.13 (t, J=7 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:40])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[NH:17][CH:16]2[C:37]([OH:39])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:46][C@@H:45]([CH2:47][CH2:48][NH2:49])[CH2:44][O:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:46][C@H:45]([CH2:44][OH:43])[CH2:47][CH2:48][NH:49][C:37]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:40])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][CH:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[NH:17]1)=[O:39]
Reactant: N#CC1(c2ccc(Cl)cc2F)C(CC2CCOCC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2CCOCC2)NC(C(=O)NCC[C@H](O)CO)C1c1cccc(Cl)c1F
Yield: 171.7 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 101c (0.15 g, 0.25 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.11 g, 0.74 mmol), HATU (0.17 g, 0.44 mmol) and iPr2NEt (0.21 mL, 1.2 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.25 g, 80%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[C:19]([CH3:24])=[CH:20]N(C)C)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:26]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27]1.Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:24])=[CH:20][N:32]=[C:30]([NH:29][CH:26]3[CH2:28][CH2:27]3)[N:31]=2)[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=CN(C)C)C(=O)c1c[nH]c(C(=O)NC(CO)c2ccccc2)c1
Reactant: N=C(N)NC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cnc(NC2CC2)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 7.1 %

Procedure:
4-(3-Dimethylamino-2-methyl-acryloyl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide (100 mg, 0.29 mmol) was combined with cyclopropyl guanidine•HCl (80 mg) and potassium carbonate (121 mg) in N,N-dimethylacetamide (2 mL). The resulting suspension was heated and stirred at 100° C. for 24 hours. The crude material was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over MgSO4 then concentrated in vacuo. Purification by preparative TLC (silica, 1:1 EtOAc:Hexanes) afforded III-a-162 as a yellow solid (7.8 mg). HPLC Method B, Rt=4.29 minutes; LC/MS(m/z) 378.2 (M+1), 376.2 (M−1); 1H NMR consistent with structure.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)(C)C>[CH3:18][C:5]1[C:6]2[C:15](=[CH:14][C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C)c2c1C(=O)c1ccccc1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C)c2cc3ccccc3cc12
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of 1,4-dimethylanthraquinone (1 g, 4.24 mmol) suspended in 40 mL of isopropanol was added sodium borohydride (1.6 g, 42.4 mmol) in portions over 1 h at room temperature with stirring. The reaction mixture was left to stir at this temperature for an additional 30 min before heating to reflux overnight. The solution was then cooled to room temperature and quenched by pouring into 5% HCl solution. The mixture was left to stir for 1 hr and the solution was filtered to give a yellow solid. The solid was further recrystallized from ethanol to give the product 11 as a bright yellow solid (0.795 g, 92%): m.p. 70-72° C. (lit. m.p. 74° C.); 1H NMR (300 MHz, CDCl3): 8.56 (2 H, s), 8.06 (2 H, dd, J=6.5 and 3.3 Hz), 7.50 (2 H, dd, J=6.5 and 3.3 Hz), 7.22 (2 H, s), 2.82 (6 H, s); HR-MS (EI) calcd. for C16H14 (M+): 206.11, found: 206.11.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>COCCOC.Cl>[CH2:13]([O:12][C:10](=[O:11])/[CH:9]=[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)\[CH3:15])[CH3:14]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Tetrakis(triphenylphoshine)palladium(0) (0.26 g, 0.22 mmol, 4 mol %) was added, under nitrogen, to a stirred solution of (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.5 g, 5.57 mmol) {prepared as detailed in example 50 a} in DME (70 ml), and the resulting orange coloured solution stirred at room temperature for 10 min. Aqueous 2M sodium carbonate (16.7 ml, 33.4 mmol) was then added, the mixture stirred for 10 min, then 4-chlorophenyl boronic acid (1.3 g, 8.36 mmol) was added, and the reaction mixture heated to 80° C. for 18 h, under reflux. The reaction mixture was diluted with 1N HCl (100 ml) and the products extracted into ethyl acetate (2×100 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the crude product, which was purified by column chromatography on silica gel (20% ethyl acetate in n-heptane eluent) to give the product, (E)-ethyl-3-(4′-chloro-biphenyl-4-yl)-but-2-enoate as a colourless solid; 1.17 g (70%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:12]([CH3:15])([O-:14])=[O:13].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3](/[CH:4]=[CH:15]/[N+:12]([O-:14])=[O:13])=[C:2]([OH:1])[CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(/C=C/[N+](=O)[O-])c(O)c1
Temperature: 100 °C

Procedure:
A mixture of 2-hydroxy-4-methoxybenzaldehyde (5.0 g, 32.9 mmol), nitromethane (5.5 g 90.0 mmol), ammonium acetate (6.9 g 90.0 mmol) and 40 mL of glacial acetic acid was heated at 100° C. for 4 hours. The reaction was then cooled, concentrated and partitioned between ethyl acetate and water. The organic extract was washed with 10% sodium bicarbonate solution, water, and brine and dried over sodium sulfate. The organic solution was concentrated and chromatographed on a silica gel column eluting with 1:4 ethyl acetate/hexane to afford the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.78 (s, 3H) 6.49-6.55 (m, 2H) 7.65 (d, J=8.33 Hz, 1H) 8.00-8.06 (d, J=13.5 Hz, 1H) 8.13-8.19 (d, J=13.5 Hz 1H) 11.00 (s, 1H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:25]([C:29]1[N:30]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:31]([CH:35]=[O:36])=[C:32]([Cl:34])[N:33]=1)[CH2:26][CH2:27][CH3:28].C1CCN2C(=NCCC2)CC1>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]([NH:47][S:44]([C:41]1[CH:42]=[CH:43][C:38]([CH2:37][N:30]2[C:31]([CH:35]=[O:36])=[C:32]([Cl:34])[N:33]=[C:29]2[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:39][CH:40]=1)(=[O:46])=[O:45])=[O:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
N-Boc-glycine (2.8 g, 16 mmol, 1.0 eq) was dissolved into 50 mL THF. CDI (2.6 g, 16 mmol, 1.0 eq) was added, and the mixture heated to 80° C. for 2 hours. The solution was cooled to room temperature and added to a solution of intermediate (2c) (5.7 g, 16 mmol, 1.0 eq) in 100 mL THF followed by DBU (2.4 mL, 16 mmol, 1.0 eq). The mixture was stirred at room temperature overnight. The mixture was then concentrated, redissolved into 100 mL EtOAc, washed with saturated bicarbonate, saturated aqueous NaCl, dried over MgSO4, and evaporated. The residue was chromatographed (10% MeOH:EtOAc with 0.7% NH3) to yield intermediate (2d) (5.6 g).
Reaction SMILES: CO.[OH-].[Na+].[NH2:5][C:6]1[C:11]([C:12]2[O:16][N:15]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.Cl[CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>CN(C)C=O>[CH3:33][C:31]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:26][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C:14]3[CH:13]=[C:12]([C:11]4[C:6]([NH2:5])=[N:7][CH:8]=[CH:9][CH:10]=4)[O:16][N:15]=3)=[CH:19][CH:20]=2)[CH:32]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccnc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 29.7 %

Procedure:
Methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.18 mL) were added to 4-(5-(2-amino-pyridine-3-yl)isoxazole-3-ylmethyl)-phenol (50 mg, 0.19 mmol) described in Manufacturing Example 5-1-1, which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue were added 2-chloromethyl-4-methyl-pyridine (31.8 mg, 0.22 mmol) described in Manufacturing Example 11-1-4 and N,N-dimethylformamide (2 mL), which was stirred for 10 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (21 mg, 30.2%).
Reaction SMILES: [CH3:1][C:2]1[N:9]=[C:8]([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:22][OH:23]>>[OH:23][N:22]=[C:4]([C:3]1[C:2]([CH3:1])=[N:9][C:8]([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:14])[CH3:15])=[CH:7][CH:6]=1)[NH2:5]
Reactant: Cc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C#N
Reactant: NO
Product: Cc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C(N)=NO

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 2-methyl-6-{[(triisopropylsilyl)oxy]methyl}nicotinonitrile (0.63 g, 2.1 mmol) that was obtained in Example 24 (24c) and a 40% aqueous solution of hydroxylamine (0.5 mL). Subsequently, the crude product of the title compound thus obtained was purified by recrystallization from a mixed solvent of ethyl acetate and hexane (1:9) to afford the title compound (0.61 g) in a yield of 86% as a white crystalline solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O:23]C)=[O:22])[CH:14]=[N:13]1)[CH2:2]2.O.[OH-].[Li+:27].O.CO>O1CCCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O-:23])=[O:22])[CH:14]=[N:13]1)[CH2:2]2.[Li+:27]
Reactant: COC(=O)c1cccc2cnn(CCN[C@@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2cnn(CCN[C@@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.3 %

Procedure:
To a stirred solution of (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate (370 mg, 1.12 mmol) from Step F above in tetrahydrofuran (5 mL) was added lithium hydroxide monohydrate (142 mg, 3.4 mmol), water (5 mL) and methanol (5 mL). The mixture was stirred at room temperature for 17 h and then concentrated under reduced pressure. The residue was co-evaporated with toluene (2×10 mL) and dried overnight under vacuum to afford crude lithium (S)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate (360 mg, quantitative yield) which was used in the next step without further purification: 1H NMR (500 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.53 (dd, J=8.0, 1.0 Hz, 1H), 7.32 (dd, J=6.5, 1.0 Hz, 1H), 6.96 (t, J=7.0 Hz, 1H), 4.85-4.75 (m, 2H), 4.50-3.50 (br s 2H), 2.90-2.70 (m, 3H), 2.65-2.45 (m, 4H), 2.11-2.07 (m, 1H), 1.68-1.65 (m, 2H), 1.51-1.46 (m, 1H), 1.31-1.26 (m, 1H), 1.10-1.06 (m, 1H); MS (ESI+) m/z 315 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1>CO.C(OCC)(=O)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:3][CH:4]=1)#[N:10]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: N#CCc1ccc(N)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CCc1ccc(Nc2ccc(C(N)=O)cn2)cc1

Procedure:
Combine 4-aminophenylacetonitrile (5.0 g, 37.9 mmol) and 6-chloro-nicotinamide (6.3 g, 40.3 mmol) in a flask and heat at 150° C. for 5 hours. Cool, dissolve the residue in methanol, dilute with ethyl acetate, then wash with saturated aqueous sodium bicarbonate solution. Dry the organic layer over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (10 g). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-(4-cyanomethyl-phenylamino)-nicotinamide. Triturate the resulting solid with hot isopropanol, collect the precipitate to yield 6-(4-cyanomethyl-phenylamino)-nicotinamide (1.8 g): 1H NMR (DMSO-D6, 300.00 MHz): 9.48 (s, 1H), 8.69 (d, 1H, J=2.1 Hz), 8.03-7.71 (m, 4H), 7.31-7.21 (m, 3H), 6.85 (d, 1H, J=8.8 Hz), 3.97 (s, 2H).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:7][CH2:8][CH3:9])[C:4]([OH:6])=[O:5].[CH3:10]O>>[ClH:1].[CH3:10][O:5][C:4](=[O:6])[C@@H:3]([NH2:2])[CH2:7][CH2:8][CH3:9]
Reactant: CO
Reactant: CCC[C@H](N)C(=O)O
Agent: Cl
Product: CCC[C@H](N)C(=O)OC
Temperature: 0 °C
Yield: 85 %

Procedure:
Dry hydrochloric acid gas was bubbled through a mixture of (S)-2-amino-pentanoic acid (1.00 g, 8.53 mmol) in methanol cooled to 0° C. for 5 min. The vessel was sealed and the mixture heated to 50° C. overnight. The mixture was cooled, the solvent removed and the residue treated with methanol (repeated 3×). The residue was triturated with diethyl ether, dried under high vacuum to yield (S)-2-amino-pentanoic acid methyl ester hydrochloride (1.21 g, 85%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (t, J=6.9 Hz, 3H), 1.12-1.51 (m, 2H), 1.76 (m, J=6.0 Hz, 2H), 3.74 (s, 3H), 3.98 (t, J=6.0 Hz, 1H), 8.59 (br. s., 3H).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:23])=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:23][CH2:3][C:2]#[CH:1])=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Reactant: C#CCBr
Product: C#CCOc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
This was prepared as for Example 24 but using propargyl bromide (0.48 g, 0.0044 mol) and 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.50 g, 0.0018 mol) and recrystallising the product from ethanol/water; yield=210 mg as a white crystalline solid, mp=183°-185° C. Found: C, 69.21; H, 3.68; N, 4.34. C18H12ClNO2 +0.1 H2O requires C, 69.39; H, 3.95; N, 4.50. δ (360 MHz, DMSO-d6), 3.50 (1H, t, J=2.3 Hz, CCH), 4.26 (2H, d, J=2.5 Hz, OCH2C), 7.28 (1H, dd, J=8.5 and 1.9 Hz, H6), 7.32-7.48 (6H, m, aromatics), 7.86 (1H, d, J=8.6 Hz, H5), 11.96 (1H, s, br, NH). MS (CI) m/z=310 [MH]+.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[CH:21]([OH:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([O:11]C)=[O:10])[CH:4]=1.[OH-].[Na+]>CO>[OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[CH:21]([OH:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(C(O)c2cccc(C(=O)OC)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(C(O)c2cccc(C(=O)O)c2)n1
Yield: 51.8 %

Procedure:
Under the conditions of example 2, 80 mg of 2-[(1RS)-1-hydroxy-1-(3-methoxycarbonylphenyl)-methyl]-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 4 ml of methanol is saponified with 4 ml of 0.5 n sodium hydroxide solution and worked up. 40 mg of the title compound is obtained as colorless foam.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7](C)[C:8](=[S:12])[N:9]([CH3:11])[CH3:10].[CH3:14][N:15](C)[C:16](=[S:20])[N:17]([CH3:19])[CH3:18].[CH3:22][N:23](C)C(=S)N(C)C.[H+].[B-](F)(F)(F)F>O.[Au+]>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:14][N+:15]1[N:7]=[C:8]([S-:12])[N:9]([CH3:11])[C:10]=1[CH3:22].[CH3:22][N+:23]1[N:15]=[C:16]([S-:20])[N:17]([CH3:19])[C:18]=1[CH3:6]
Reactant: CN(C)C(=S)N(C)C
Agent: [Au+]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Product: Cc1n(C)c([S-])n[n+]1C
Temperature: 60 °C
Yield: 86 %

Procedure:
First the gold(I) starting compound, aurous bis(tetramethylthiourea) tetrafluoroborate, was made as follows. HAuCl4.3H2O (0.255 g) was dissolved in 5 mL water and added dropwise to tetramethylthiourea (0.327 g) which was partly dissolved in water. Dark orange and red precipitates formed initially, but after stirring at about 50° to 60° C. the precipitates dissolved and the solution become completely clear and colorless. 0.2 mL HBF4 solution (49% aqueous) was added. After cooling a few hours, white platelets of the product were filtered (84% yield). This intermediate gold(I) compound (0.228 g) was dissolved in 4 mL water by heating to about 60° C., and then added to a room temperature solution of 1,4,5-trimethyl-1,2,4-triazolium-3-thiolate (0.126 g). A white precipitate began to form, and was filtered after standing in the refrigerator a few hours. The product yield was 86%. The product could be recrystallized from hot water. Elemental analysis conformed to the formula for compound 1, and a single-crystal x-ray diffraction study confirmed the structure as a linear, two-coordinate complex with gold-sulfur bond lengths averaging 2.27 angstroms.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Se](=O)=[O:14].O1CCOCC1>O.CN(C)C=O>[O:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=[C:4]1[C:1](=[O:3])[CH:2]=[O:14]
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=CC(=O)c1cc2ccccc2o1
Yield: 60.1 %

Procedure:
A mixture of 2-acetylbenzofuran (100 g) and selenium dioxide (69.3 g) was dissolved in water (20 ml) and dioxan (500 ml) and heated under reflux for 24 h. The reaction mixture was filtered and the solvent evaporated to give a dark-red solid which was taken up in dimethylformamide and heated on a steam bath for 8 h. The solution was filtered, the solvent evaporated and the residue triturated with ether to give the title compound (65.4 g).