Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[NH2:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C(#N)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[NH:21][C:22]2=[O:23])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1CCCCC1NC1CCN(Cc2ccccc2)CC1
Solvent: CC#N
Product: O=C1NC2CCCCC2N1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
In this reference example, a solution of 631 mg of 1-benzyl-4-(2-amino-cylohexylamino)-piperidine in a free form obtained in Reference Example 17 and 550 mg of 1,1'-carbonyldiimidazole in 10 ml of acetonitrile is stirred at room temperature for 12 hours. The deposited crystals are separated by filtration, washed with acetonitrile and then dried to obtain 383 mg of crude crystals. The crude crystals are recrystallized from 34 ml of isopropanol to obtain 300 mg of the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2Br)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Cl[P:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45].C([Li])CCC>>[C:1]([C:5]1[CH:6]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[P:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2Br)cc1C(C)(C)C
Reactant: CCOP(Cl)OCC
Agent: [Li]CCCC
Product: CCOP(OCC)c1ccccc1P(c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1

Procedure:
For example, referring to the reaction sequence shown below, 2-bromophenol (4) is reacted with trifluoromethanesulfonic anhydride to form 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), which is then reacted with bis(3,5-di-t-butyl-4-methoxyphenyl)phosphine oxide in the presence of a palladium complex catalyst to obtain bis(3,5-di-t-butyl-4-methoxyphenyl)(2-bromophenyl)phosphine oxide (6). Next, the compound (6) is reduced with trichlorosilane in the presence of N,N′-dimethylaniline to obtain bis(3,5-di-t-butyl-4-methoxyphenyl)(2-bromophenyl)phosphine (7). The compound (7) is reacted with diethyl chlorophosphonite in the presence of n-butyllithium to obtain diethyl 2-[bis(3,5-di-t-butyl-4-methoxyphenyl)phosphino]phenylphosphonite (8). Then, the compound (8) is reduced with lithium aluminum hydride in the presence of trimethylsilyl chloride to form 2-[bis(3,5-di-t-butyl-4-methoxyphenyl)phosphino]phenylphosphine (9). Thereafter, in the presence of n-butyllithium, the compound (9) is reacted with dimesylate of (2R,5R)-2,5-hexanediol, which is producible, for example, according to the method described in the literature (Tetrahedron: Asymmetry, 1991, 2, 569), whereby the aimed (S,S)-Me-UCAP-DTBM (3) can be produced in a high efficiency.
Reaction SMILES: [CH2:1]([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1([OH:21])[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.CI.O>C1COCC1.CCOC(C)=O>[CH3:1][C:10]1[S:6][C:7]([C:11]2([OH:21])[CH2:12][CH2:13][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:19][CH2:20]2)=[N:8][CH:9]=1
Reactant: [Li]CCCC
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cnc(C2(O)CCC3(CC2)OCCO3)s1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A solution of n-butyllithium (5.70 mL of 1.6 M solution in hexane, 9.12 mmol) was added to 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (1.00 g, 4.14 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, methyl iodide (0.71 mL, 9.12 mmol) was added to the lithiated compound solution via syringe at −78° C. The reaction mixture was allowed to warm to room temperature slowly and stirred overnight. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl, dried (MgSO4), concentrated and flash chromatographed using 20% EtOAc/hexane to give 0.77 g of the title compound in 71% yield. MS (EI) (M+H)+=256.1.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH2:40])=[S:39])([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH:40][C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:3])=[S:39])([CH3:30])[CH3:29]
Reactant: CC(C)c1ccccc1NC(N)=S
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: CC(C)c1ccccc1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(2-isopropylphenyl)thiourea isolated as a white solid (0.033 g, 11%): 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.14 (s, 1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.94 (m, 2H), 7.68-7.57 (m, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dq, J=7.8, 1.5 Hz, 2H), 7.34 (dd, J=7.8, 1.6 Hz, 1H), 7.26 (td, J=7.5, 1.5 Hz, 1H), 7.20 (td, J=7.5, 1.6 Hz, 1H), 7.03 (t, J=5.7 Hz, 1H), 3.47 (q, J=6.6 Hz, 2H), 2.98 (p, J=6.9 Hz, 1H), 2.89 (t, J=6.9 Hz, 2H), 1.15 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 569 ([M+H]+), 567 ([M−H]−).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:12]=[N+:11]([O-])[CH:10]=[C:9]2[NH:14][N:15]=[CH:16][C:8]=12>O>[Br:6][C:7]1[CH:12]=[N:11][C:10]([Cl:3])=[C:9]2[NH:14][N:15]=[CH:16][C:8]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(Br)c2cn[nH]c2c1
Solvent: O
Product: Clc1ncc(Br)c2cn[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorus oxychloride (2 ml) was added to 4-bromo-1H-pyrazolo[3,4-c]pyridine 6-oxide (148 mg) obtained in the 1st step, followed by stirring at room temperature for 3 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. An insoluble precipitate was removed and then the solvent was distilled away under reduced pressure. A yellow solid of 4-bromo-7-chloro-1H-pyrazolo[3,4-c]pyridine (126 mg) was thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH:7]=O)([O-:3])=[O:2].[Br-].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[CH2:19]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[Cl-].[Na+]>C1C=CC=CC=1.C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[CH:19]\[C:18]2[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])([O-:3])=[O:2]
Reactant: COc1cc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1cc(/C=C\c2ccc(C)c([N+](=O)[O-])c2)cc(OC)c1OC
Yield: 49.6 %

Procedure:
1.0 g of 3-nitro-4-methylbenzaldehyde and 3.3 g of 3,4,5-trimethoxybenzyltriphenylphosphine bromide were dissolved in 50 ml of benzene, and a benzene solution containing 302 mg of sodium hydride dispersed therein was added thereto and reacted for 15 hours at room temperature. The reaction liquid was neutralized with acetic acid, saturated sodium chloride solution was added thereto, and the resulting liquid was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (diethyl ether:hexane=1:2 by volume) to obtain 0.99 g of the intended compound. The yield of the product was 47.8%.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[Cl:9].C[O-].[Na+].[CH3:13][CH:14]([CH3:31])[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:30])[C:26](OC)=[O:27])=[CH:21][C:19]=2[N:20]=1>O1CCCC1.[Cl-].[NH4+]>[Cl:9][C:3]1[C:4]([CH2:7][CH3:8])=[N:5][S:6][C:2]=1[NH:1][C:26](=[O:27])[CH:25]([C:22]1[CH:23]=[CH:24][C:18]2[S:17][C:16]([CH2:15][CH:14]([CH3:13])[CH3:31])=[N:20][C:19]=2[CH:21]=1)[CH3:30]
Reactant: COC(=O)C(C)c1ccc2sc(CC(C)C)nc2c1
Reactant: CCc1nsc(N)c1Cl
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1nsc(NC(=O)C(C)c2ccc3sc(CC(C)C)nc3c2)c1Cl
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 65 %

Procedure:
5-Amino-4-chloro-3-ethylisothiazole (0.81 g, 0.005 mol) was added to a suspension of sodium methoxide (0.56 g, 0.010 mol) in tetrahydrofuran (5 ml) and the mixture stirred at room temperature for 25 minutes. A solution of methyl 2-[2-(2-methylpropyl)benzothiazol-5-yl]propionate (1.15 g, 0.004 mol) in tetrahydrofuran (4 ml) was added dropwise and the mixture stirred at room temperature for 1½ hours. The mixture was diluted with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. Trituration with diethyl ether gave the desired product (1.06 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:23]1([C:29]2[CH:47]=[C:46](B(O)O)[C:32]3[S:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[CH:36][C:35]=4[C:31]=3[CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[C:23]1([C:29]2[CH:47]=[C:46]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[N:12]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:11]5[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=5[N:9]=4)=[CH:4][CH:3]=3)[C:32]3[S:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[CH:36][C:35]=4[C:31]=3[CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cc(-c2ccccc2)cc2c1sc1ccc(-c3ccccc3)cc12
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2ccc3sc4c(-c5ccc(-c6nc7ccccc7n6-c6ccccc6)cc5)cc(-c5ccccc5)cc4c3c2)cc1

Procedure:
In a 50-mL three-neck flask were put 1.8 g (5.0 mmol) of 2-(4-bromophenyl)-1-phenyl-1H-benzimidazole, 2.2 g (5.8 mmol) of 2,8-diphenyldibenzothiophen-4-boronic acid, and 76 mg (0.2 mmol) of tri(ortho-tolyl)phosphine. The air in the flask was replaced with nitrogen. To this mixture were added 5.8 mL of a 2.0 mmol/L aqueous solution of potassium carbonate, 19 mL of toluene, and 6 mL of ethanol. Under reduced pressure, this mixture was stirred to be degassed. Then, 11 mg (50 μmol) of palladium(II) acetate was added to this mixture, and the mixture was stirred at 80° C. for 4 hours under a nitrogen stream.
Reaction SMILES: [C:1]([N:4]([CH2:37][C@@H:38]1[O:42][C:41](=[O:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:57][C:56]4[C:52](=[N:53][N:54]([CH3:58])[CH:55]=4)[CH2:51]3)=[C:46]([F:59])[CH:45]=2)[CH2:39]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([O:17][P:18]([O:28]CC2C=CC=CC=2)([O:20]CC2C=CC=CC=2)=[O:19])=[CH:13][CH:12]=1)=[O:6])(=[O:3])[CH3:2]>C1CC=CCC=1.C1COCC1.[Pd]>[C:1]([N:4]([CH2:37][C@@H:38]1[O:42][C:41](=[O:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:57][C:56]4[C:52](=[N:53][N:54]([CH3:58])[CH:55]=4)[CH2:51]3)=[C:46]([F:59])[CH:45]=2)[CH2:39]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([O:17][P:18]([OH:28])([OH:20])=[O:19])=[CH:13][CH:12]=1)=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)c1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: C1=CCC=CC1
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)c1ccc(OP(=O)(O)O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 15 (1 equiv) and 10% Pd/C (1 weight equiv of 15) in 1,4-cyclohexadiene and THF is stirred at rt for 6 h. The reaction mixture is filtered, concentrated in vacuo, purified directly by HPLC (C-18 column, 0-100% gradient elution, MeCN:H2O), and fractions containing product are lyophilized to give the title compound. Theoretical MS 646 (M+1)+
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[CH3:22][O:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:25]=1.N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C>[CH3:31][O:30][C:28]1[N:29]=[C:24]([O:23][CH3:22])[N:25]=[C:26]([NH:32][C:33]([NH:1][S:2]([C:5]2[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:19])([F:20])[F:21])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:3])=[O:4])=[O:34])[N:27]=1
Reactant: COc1nc(NC(=O)Oc2ccccc2)nc(OC)n1
Reactant: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(N)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At room temperature, 166 mg (0.5 mmol) of methyl 2-(aminosulfonyl)-4-[(2,2,2-trifluoroethlidene)hydrazino]-benzoate and 138 mg (0.5 mmol) of phenyl (4,6-dimethoxy-1,3,5-triazin-2-yl)carbamate were dissolved in 1.5 ml of N,N-dimethylacetamide. Then, 86.1 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene were added, followed by stirring for 5 minutes. The resultant mixture was allowed to stand for 6 hours. Thereafter, 0.2 ml of 35% hydrochloric acid was added to 30 ml of ice water, followed by the addition of the reaction mixture in 0.2 ml portions under stirring. After the reaction mixture was stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. Using as an eluent a 1:9 mixed solvent of methyl acetate and benzene, the crude product was purified by chromatography on a column of silica gel ("WAKO GEL C-300", trade name; product of Wako Pure Chemical Industries, Ltd.). The title compound was obtained as a white solid. Yield: 103 mg (41%). Melting point: 117°-119° C. (foamed). Its physicochemical properties are shown in Table 4.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (3 g, 6.6 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.65 g (59%); off white powder; mp 191° C.; MS: 428 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[N:24]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[N:25]1>>[N:24]1([CH2:29][CH2:30][CH2:31][NH:32][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH:10]=[N:11]3)=[N:16][CH:17]=2)[CH:28]=[CH:27][CH:26]=[N:25]1
Reactant: NCCCn1cccn1
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCCCn4cccn4)cn3)c2O)cc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(1H-pyrazol-1-yl)propan-1-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 2.00-2.10 (m, 2 H) 3.25-3.30 (m, 2 H) 4.19 (t, J=6.95 Hz, 2 H) 6.23 (t, J=2.02 Hz, 1 H) 7.45 (d, J=1.77 Hz, 1 H) 7.77 (d, J=1.52 Hz, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (d, J=7.33 Hz, 2 H) 8.37-8.44 (m, 1 H) 8.45-8.58 (m, 1 H) 8.66 (br. s., 1 H) 8.74 (t, J=5.31 Hz, 1 H) 8.88-8.94 (m, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 414.2.
Reaction SMILES: [BH4-].[Li+].CO.[CH2:5]([O:12][C:13]1[CH:28]=[CH:27][C:16]([C:17](OCC2C=CC=CC=2)=[O:18])=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.[Cl-].[NH4+]>[CH2:5]([O:12][C:13]1[N:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:27][CH:28]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)nc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(OCc2ccccc2)nc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Lithium borohydride (517 mg, 23.5 mmol) and MeOH (752 mg, 23.5 mmol) were added to a solution of benzyl 6-(benzyloxy)nicotinate (5 g, 15.7 mmol) in THF (50 mL) under N2 at 0° C. The mixture was stirred at 70° C. for 2 hours. The mixture was diluted with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) to afford (6-(benzyloxy)pyridin-3-yl)methanol. MS ESI calc'd. for C13H14NO2 [M+H]+ 216. found 216. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J=2.0 Hz, 1H), 7.69-7.67 (m, 1H), 7.45-7.33 (m, 5H), 6.86 (d, J=8.4 Hz, 1H), 5.35 (s, 2H), 5.23-5.20 (m, 1H), 4.52-4.44 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C:22]([NH2:27])([CH2:25][CH3:26])[CH2:23][CH3:24]>>[CH3:19][O:20][C:21](=[O:28])[C:22]([NH:27][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH2:25][CH3:26])[CH2:23][CH3:24]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CCC(CC)(NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and 2-amino-2-ethyl-butanoic acid methyl ester hydrochloride (1:1) (CAN 92398-54-4) as starting materials, and isolated (86 mg, 93%) as yellow oil; LC-MS (UV peak area, ESI) 100%, 362.2071 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17](=O)[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[NH:23](/[N:24]=[C:17]1\[CH2:18][CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:10][C:11]2[O:15][CH:14]=[C:13]([CH3:16])[C:12]\1=2)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NN
Reactant: Cc1ccc(C)c(C2CC(=O)c3c(C)coc3C2)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)c(C2C/C(=N\NC(=N)N)c3c(C)coc3C2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a mixture of 6-(2,5-dimethylphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.36 g) and aminoguanidine hydrochloride (157 mg) were added ethanol (28 ml) and 6N hydrochloric acid (0.12 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-4-guanidinoimino-6-(2,5-dimethylphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 38) (0.21 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH2:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1ccc(C)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared as described in Example 67 using 1-chloro-4-methyl-2-nitrobenzene and tributyl(vinyl)stannane, further purified by flash column chromatography and reverse phase chromatography and isolated as a yellow liquid (1.26 g, 65%): 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=0.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.46-7.35 (m, 1H), 7.13 (dd, J=17.3, 11.0 Hz, 1H), 5.71 (dd, J=17.3, 0.9 Hz, 1H), 5.43 (dd, J=11.0, 0.9 Hz, 1H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 147.71, 138.91, 133.92, 132.31, 130.52, 128.22, 124.63, 118.10, 20.88; EIMS m/z 163 ([M]+).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][C:7]3([C:17]42[NH:21][C:20](=S)[C:19]([CH3:23])=[N:18]4)[CH2:12][CH2:11][C:10]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:26]>>[Br:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][C:7]3([C:17]42[N:21]=[C:20]([NH2:26])[C:19]([CH3:23])=[N:18]4)[CH2:12][CH2:11][C:10]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC2(CC1)OCCO2
Reactant: N
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC2(CC1)OCCO2
Temperature: 110 °C
Yield: 118.1 %

Procedure:
6″-Bromo-5′″-methyl-3″H-trispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-indene-1″,2′″-imidazole]-4″(3′″H)-thione (Example 115 Step 4, 0.5 g, 1.19 mmol) was taken up in ammonia (7 M in MeOH, 15 mL, 105 mmol) and the resulting mixture was heated in the microwave reactor at 110° C. for 30 min. The solvent was evaporated in vacuo and the same procedure (addition of ammonia, heating and evaporation) was repeated 3 times. The solvent was evaporated to yield the title compound (0.568 g, quantitative yield) that was used without further purification: 1H NMR (500 MHz, CDCl3) δ ppm 1.35-1.49 (m, 2 H), 1.61 (d, 2 H), 1.69-1.81 (m, 2 H), 2.33 (s, 3 H), 3.14 (s, 2 H), 3.87-3.98 (m, 4 H), 6.88 (d, 1 H), 7.19 (d, 1 H), 7.35 (dd, 1 H); MS (ES+) m/z 404 [M+H]+.
Reaction SMILES: C1COCC1.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Mg]Br.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].C1(C)C=CC=CC=1>CCCCCC>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: COc1ccccc1Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc2ccccc2c1
Reaction time: 48 h
Yield: 96 %

Procedure:
Using a THF solution of 2-naphthylmagnesium bromide (1.47 mL, 1.02 M, 1.5 mmol), and 1-chloro-2-methoxybenzene (142.6 mg, 1.0 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 70° C. for 48 hours in the same manner as in Example 2. After performing silica gel column chromatography (toluene=10, 20 and 40% in hexane), the above compound was obtained as a white solid (0.224 g, yield=96%, purity=>99% (GC analysis)).