Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH2:14])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:14][C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C=Cc1cc(Cl)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cc(Cl)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 65.9 %

Procedure:
3-(2-Amino-5-chloro-phenyl)-acrylic acid ethyl ester (10.4 g, 46 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (13.8 g, 69 mmol) were set stirring in CH2Cl2 (230 mL). Sodium triacetoxyborohydride (14.6 g, 69 mmol) was added in portions over 10 min. Acetic acid (1.3 mL, 25 mmol) was then added and the mixture left to stir. After 18 h saturated NaHCO3 was added and the organics separated. The organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 20-50% EtOAc/hexanes) to obtain 12.4 g (66%) of a light beige solid. TLC (silica, 25% EtOAc/hexanes): Rf=0.5. MS (electrospray): exact mass calculated for C21H29ClN2O4, 408.18. m/z found, 409.1 [M++H]. 1H NMR (400 MHz, CDCl3): 7.64 (d, J=15.65 Hz, 1H), 7.29 (d, J=2.35 Hz, 1H), 7.14 (dd, J=6.26 Hz, 2.54 Hz, 1H), 6.59 (d, J=9.00 Hz, 1H), 6.28 (d, J=15.65 Hz, 1H), 4.23 (dd, J=7.04 Hz, 7.04 Hz, 2H), 4.11-3.98 (m, 2H), 3.81 (br s, 1H), 3.46-3.36 (m, 1H), 2.89 (t, J=11.74 Hz, 2H), 2.04-1.95 (m, 2H), 1.44 (s, 9H), 1.42-1.33 (m, 2H), 1.30 (t, J=7.24 Hz, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[Cl:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([Cl:27])[CH:21]=[CH:22][CH:23]=2)[N:18]=1.[CH3:28][CH:29]=[O:30]>C1COCC1.CCCCCC>[Cl:16][C:17]1[C:26]([CH:29]([OH:30])[CH3:28])=[CH:25][C:24]2[C:19](=[C:20]([Cl:27])[CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: CC=O
Reactant: Clc1ccc2cccc(Cl)c2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(O)c1cc2cccc(Cl)c2nc1Cl
Reaction time: 0.75 h

Procedure:
To a cold solution of diisopropylamine (6.6 mL, 1.1 eq) in THF (100 mL) was added dropwise a solution of BunLi (1.1 eq, 2.5 M, 18.7 mL) in hexane at −20° C. The resulted LDA solution was kept in 0° C. for 30 min and cooled to −78° C. before addition of a solution of 2,8-dichloroquinoline (8.4 g, 42.4 mmol) in THF (44 mL) dropwise. The temperature was controlled below −72° C. by adjusting of adding rate (15 min). After 45 min, MeCHO (3.6 mL, 1.5 eq) was added dropwise. After 30 min, the reaction was quenched with NH4Cl and partitioned between EtOAc (150 mL) and water (100 mL). The combined organics were washed with water, brine, dried over Na2SO4. Removal of solvent gave colorless oil which was purified by column chromatography on silica gel (DCM/Hexane, 3/2) to give an oil. Hexane was added (80 mL) and the mixture was left over night. Filtration gave a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 5.40 (q, J=8.0 Hz, 1H), 1.63 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=242 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.Br[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[N:26]1([C:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:10]3[N:9]=[C:8]([N:4]4[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:33]5[N:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH2:3]4)[CH:16]=[CH:15][C:11]=3[C:12]([NH2:14])=[O:13])=[CH:23][CH:22]=2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Brc1ncccn1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(N2CCC[C@@H](Nc3ncccn3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
A mixture of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (50 mg, 0.118 mmol), 2-bromopyrimidine (22.47 mg, 0.141 mmol), and DIEA (0.041 mL, 0.236 mmol) in THF (1 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water, 10% LiCl, and concentrated. The residue was purified by prep-HPLC and the product containing fractions were collected, basified with 1N NaOH, extracted with CH2Cl2, washed with water, and concentrated to give 18 mg of (R)-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(3-(pyrimidin-2-ylamino)piperidin-1-yl)nicotinamide as a light yellow solid. LCMS: (M+H)+=503.23. 1H NMR (500 MHz, CDCl3) δ ppm 11.19 (1H, s), 8.27 (2H, d, J=4.58 Hz), 7.68 (2H, d, J=8.71 Hz), 7.51 (1H, d, J=8.71 Hz), 7.27 (2H, d, J=8.71 Hz), 6.56 (1H, t, J=4.81 Hz), 6.12 (1H, d, J=9.16 Hz), 5.57 (2H, br. s.), 5.26 (1H, d, J=7.79 Hz), 4.20 (1H, dd, J=12.83, 3.21 Hz), 4.09 (1H, dt, J=7.79, 3.89 Hz), 3.89-3.98 (1H, m), 3.49-3.83 (8H, m), 3.42-3.48 (1H, m), 3.39 (1H, dd, J=12.83, 7.79 Hz), 2.04-2.13 (2H, m), 1.69-1.92 (2H, m).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C@@H:5]([CH:7]2[CH2:9][N@@:8]2[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[O:4][C:3]1=[O:22].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][CH2:33][C:32]1=[O:39]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[N:31]1[C:32](=[O:39])[CH2:33][N:34]([CH2:9][C@H:7]([NH:8][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C@@H:5]2[CH2:6][C@@H:2]([CH3:1])[C:3](=[O:22])[O:4]2)[C:35]([CH3:38])([CH3:37])[CH2:36]1
Reactant: C[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: CC1(C)CN(c2cc(F)ccc2Cl)C(=O)CN1
Agent: C[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3cc(F)ccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 94.2 %

Procedure:
A solution of 730 mg of (3R,5S)-3-methyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (76g) (2.24 mmol) and 689 mg of 1-(2-chloro-5-fluorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (62d) (2.68 mmol) in toluene (22 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=3/1-2/1) to obtain 1.23 g of the title compound (yield: 94%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22].C(C1C(N=CN(C)C)=NC(SCC)=NC=1)#N>>[CH2:11]([S:10][C:4]1[N:3]=[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])[C:7]([C:8]#[N:9])=[CH:6][N:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cnc(SCc2ccccc2)nc1N
Reactant: COC(OC)N(C)C
Agent: CCSc1ncc(C#N)c(N=CN(C)C)n1
Product: CN(C)C=Nc1nc(SCc2ccccc2)ncc1C#N

Procedure:
A solution of the product from Example 183B was reacted with N,N-dimethylformamide dimethyl acetal according to the procedure from Example 156B substituting the product from Example 183B for the product from Example 156B to provide the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[CH2:2]1.[C:11]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:13])=[O:12].[C:34]1(C)C=CC=C[CH:35]=1>>[CH2:34]([O:13][C:11](=[O:12])[CH2:14][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH:2]=1)[CH3:35]
Reactant: Cc1ccccc1
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1COc2ccccc21
Product: CCOC(=O)Cc1coc2ccccc12
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of benzofuran-3-one (1.00 g, 7.45 mmol) in toluene (25 mL) was added (carboxymethylene)triphenyl phosphorane (3.92 g, 11.2 mmol), and the mixture was refluxed for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (hexane, then ethyl acetate:hexane; 1:3) to give a product (0.89 g, 58%). The spectral data for this compound are identical to that reported in the literature. (Deshpande, A. R.; Paradkar, M. V. Syn.Commun., 1990, 20, 809).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]2[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=2)[CH:35]=1)[C:12](=[O:32])[CH2:13][NH:14]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OCC)(=O)C>C(#N)C.N1CCCCC1>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]2[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([O:46][CH3:47])[CH:45]=2)[CH:35]=1)[C:12](=[O:32])[CH2:13][NH2:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)ccn2)cc(OC)c1OC
Solvent: C1CCNCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)CN)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[2-(tert-butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-Nα-(9-fluorenylmethoxycarbonyl)glycine amide (5.15 g) was dissolved in a 20% acetonitrile solution (40 mL) of piperidine, and the solution was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([OH:9])[CH:3]=1.[N:10]([O-])=O.[Na+].[Sn](Cl)[Cl:15]>O.Cl>[ClH:15].[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([OH:9])[CH:3]=1)[NH2:10]
Reactant: O=N[O-]
Reactant: Cc1ccc(N)cc1O
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NN)cc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 127.1 %

Procedure:
To an ice cold slurry of 4-amino-2-hydroxytoluene (6.22 g, 50.0 mmol), ice (10.0 g) and hydrochloric acid (37% aqueous, 15.0 mL) was added an ice-cold solution of sodium nitrite (3.49 g, 50.0 mmol) in water (10.0 mL) over 30 min. The resultant slurry was added over 30 min to an ice-cold slurry of tin (II) chloride (25.3 g, 133 mmol) in water (30.0 mL) and hydrochloric acid (37% aqueous, 30.0 mL) and the reaction stirred overnight. The mixture was cooled in an ice/water bath and the solid collected by filtration, washing with ice-cold cyclohexane. The residue was dried in vacuo at 50° C. to give the title compound (water retained, 11.1 g). 1H NMR (300 MHz, d4-MeOD): 2.12 (3H, s), 6.38 (1H, dd, J=2.3, 8.0 Hz), 6.44 (1H, d, J=2.3 Hz), 7.02 (1H, d, J=8.1 Hz).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]2[N:19]=[C:18](O)[C:17]3=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=[CH:23][N:16]3[N:15]=2)[N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([P+](O[N:41]1N=[N:48][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1CCN2C(=NCCC2)CC1.N1C=CC=CC=1CN>C(#N)C.O>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]2[N:19]=[C:18]([NH:41][CH2:42][C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][N:48]=3)[C:17]3=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=[CH:23][N:16]3[N:15]=2)[N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1nc(-c2nc(O)c3c(-c4ccccc4)ccn3n2)cs1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)NS(=O)(=O)c1nc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
N-(tert-Butyl)-4-(4-hydroxy-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)thiazole-2-sulfonamide (0.0600 g, 0.140 mmol) was dissolved in acetonitrile (5 mL) and cooled to 0° C. BOP reagent (0.0620 g, 0.140 mmol) was added slowly, followed by DBU (0.0210 mL, 0.140 mmol). The reaction mixture was allowed to reach ambient temperature for 1 h then cooled to 0° C. Pyridin-2-ylmethanamine was added, (0.0150 g, 0.140 mmol). The reaction mixture was allowed to reach ambient temperature and stir for 14 h and diluted with water. The aqueous mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 1.2% methanol in CH2Cl2) to afford N-(tert-butyl)-4-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thiazole-2-sulfonamide (0.0400 g, 55.0%). The impure compound was taken to the next step as such. LCMS Condition B-13: retention time 2.13 min, [M+1]=520.2.
Reaction SMILES: [CH:1]([NH:4][S:5](Cl)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:16]([NH:20][C:21](=[NH:30])[S:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(OC)=[O:17]>ClCCCl>[CH:1]([N:4]1[S:5](=[O:7])(=[O:6])[NH:30][C:21]([S:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:20][C:16]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)Cl
Reactant: COC(=O)NC(=N)SCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)N1C(=O)N=C(SCc2ccccc2)NS1(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
37.9 parts of isopropylaminosulfonyl chloride and 26.3 parts of triethylamine were introduced simultaneously, through two feed lines, into a stirred mixture of 54 parts of N-carbomethoxy-S-benzyl-isothiourea and 740 parts of 1,2-dichloroethane, at from 5° to 10° C. After having been stirred for 4 hours at 25° C., the reaction mixture was extracted once with 200 parts of water and twice with 100 parts, each time, of 0.5 N hydrochloric acid. After drying, and concentrating under reduced pressure, 79 parts of N-carbomethoxy-N'-isopropylsulfamyl-S-benzyl-isothiourea of nD25 =1.5598, were obtained. This material crystallized on trituration with hexane, and the crystalline product melted at 76°-78° C. 76 parts of this product were dissolved in a mixture of 44 parts of 50% strength by weight sodium hydroxide solution and 200 parts of water and the reaction mixture was stirred for 5 minutes at 85° C. It was then cooled and acidified with 15% strength hydrochloric acid, and the oil which precipitated was taken up in methylene chloride. This solution was dried over magnesium sulfate, filtered through neutral alumina and concentrated under reduced pressure, giving 59.5 parts of 6-isopropyl-3-benzylmercapto-5,6-dihydro-1,2,4,6-thiatriazin-5-one-1,1-dioxide (86.3% of theory), of melting point 124°-130° C. This constitutes active ingredient No. 2.
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([O-:10])=[O:9])([O-])=O.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1.[H][H].[ClH:25]>[Ni].CO.O1CCOCC1.CCO>[ClH:25].[ClH:25].[NH2:1][C:4]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:22][CH2:18][CH2:19][CH3:20])=[O:9]
Reactant: C1CCOC1
Reactant: [H][H]
Reactant: O=C([O-])COc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCOC(=O)COc1cccc(N)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a Parr hydrogenation bottle was added 12.0 g of 2-(2,3-dinitrophenoxy)acetate, Raney Nickel (2.0 g, wet), THF (100 mL) and EtOH (150 mL). The atmosphere of the vessel was replaced by hydrogen gas. The reaction was shaken on a Parr hydrogenator at 40 psi at room temperature, overnight. The catalyst was filtered over a plug Celite and the filtrate was concentrated under reduced pressure to give a residue, which was dissolved in methanol, acidified with 4 N hydrogen chloride in 1,4-dioxane and filtered. The resulting filtrate was concentrated under reduced pressure to give tent-butyl 2-(2,3-diaminophenoxy)acetate dihydrochloride (8.7 g, 82%), and was used directly in the next step without any further purification. MS (EI): 239 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:17]1([C:23]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:24]=2[C:25](Cl)=[O:26])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:25]([C:24]3[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=[CH:31][C:23]=3[N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:26])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 1-(4-Methanesulfonyl-phenyl)-piperazine and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (76%, yellow solid, MS (m/e): 475.1 (M+H, 100%)
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH:15][C:16]([C:18]3([NH:24][S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Br:34])(=[O:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:6]1)[CH2:12]2)=[O:4].O1CCCC1.CO.[OH-].[Li+]>O>[Br:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:25]([NH:24][C:18]1([C:16]([NH:15][CH:8]2[CH:7]3[CH2:6][C:5]4([C:3]([OH:4])=[O:2])[CH2:12][CH:11]([CH2:10][CH:9]2[CH2:14]4)[CH2:13]3)=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)(=[O:27])=[O:26]
Reactant: COC(=O)C12CC3CC(C1)C(NC(=O)C1(NS(=O)(=O)c4ccccc4Br)CCCCC1)C(C3)C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C12CC3CC(C1)C(NC(=O)C1(NS(=O)(=O)c4ccccc4Br)CCCCC1)C(C3)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
In a 25-mL flask, 4-{[1-(2-bromo-benzenesulfonylamino)-cyclohexanecarbonyl]-amino}-adamantane-1-carboxylic acid methylester (140 mg, 0.253 mmol) was charged, and dissolved through addition of tetrahydrofuran (5 mL), and methanol (5 mL). Lithium hydroxide dissolved in purified water (5 mL) was added thereto, followed by stirring for 12 hours at room temperature. After the reaction was completed, the resultant solution was vacuum-evaporated, acidified with 2N hydrochloric acid aqueous solution to pH 1-2, and extracted with addition of ethyl acetate (20 ml). The organic layer was added with magnesium sulfate so as to remove remaining moisture. Through filtering and vacuum distillation, the solvent was removed so as to obtain 4-{[1-(2-bromo-benzenesulfonylamino)-cyclohexanecarbonyl]-amino}-adamantane-1-carboxylic acid (106 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[O:11].[CH:12]#[C:13][CH3:14]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH:10]([OH:11])[C:12]#[C:13][CH3:14]
Reactant: CC1=C(C=O)C(C)(C)CC=C1
Reactant: C#CC
Product: CC#CC(O)C1=C(C)C=CCC1(C)C

Procedure:
Safranal, prepared according to Compt. rend. 262, 1725 (1966), was reacted with propyne to give 2,6,6-trimethyl-1-[1-hydroxy-2-butynyl]-1,3-cyclohexadiene, following the procedure outlined in Example 18, paragraph b, for the reaction of citral with propyne. The above carbinol was oxidised with MnO2 to 2,6,6-trimethyl-1-tetrolyl-1,3-cyclohexadiene, following the procedure described in Example 18, paragraph c), for the oxidation of the dihydro analogue. The above acetylenic ketone was then partially reduced to the title compound following the method described in Example 18, paragraph a). Cis-2,6,6-trimethyl-1-crotonoyl-1,3-cyclohexadiene gave the following NMR data (CCl4): 1.06 (6 H, s), 1.69 (3 H, s), 2.09 (2 H, d, J = 2.3 cps), 2.14 (3 H, d, J = 5.5 cps), 5.81 (2 H, t + s, J = 2.3 cps), 6.2 (2 H, complex band) ppm (δ).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[O:18]1[C:22]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])=[CH:21][N:20]=[CH:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[O:18]1[C:22]([C:23]2[CH:24]=[C:25]([NH:26][C:13]3[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=4)[CH:16]=[N:15][CH:14]=3)[CH:27]=[CH:28][CH:29]=2)=[CH:21][N:20]=[CH:19]1
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3cccc(-c4cnco4)c3)n2)c1
Yield: 25.8 %

Procedure:
Using Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 3-(1,3-oxazol-5-yl)aniline (56.1 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. for 16 hours. The same workup as for Method L and a combination of column chromatography and preparative TLC afforded 23 mg of pure title compound. Yield: 25.8%. 1H NMR (250 MHz, DMSO-d6) δ 2.08 (s, 3H), 7.36 (d, 1H, 8.0 Hz), 7.48 (t, 2H, 8.3 Hz), 7.61 (s, 1 H), 7.65 (d, 1 H, 8.4 Hz), 7.82 (d, 2 H, 7.3 Hz), 8.23 (s, 1 H), 8.39 (bs, 2 H), 8.46 (s, 1 H), 8.47 (s, 1 H), 9.82 (s, 1 H), 10.09 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.0, 113.4, 117.1, 117.3, 118.3, 120.3, 121.3, 121.8, 127.9, 129.3, 129.8, 130.3, 133.7, 137.0, 139.9, 141.4, 147.9, 150.8, 151.3, 151.7, 168.5; m/z 372.2 [(M+H)+, calcd for C21H17N5O2 371.1].
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[NH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH3:15].[N:16]#[C:17][NH2:18]>C(O)C.O>[N+:1]([O-:4])([OH:3])=[O:2].[CH3:15][C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[NH:5][C:17]([NH2:18])=[NH:16]
Reactant: N#CN
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Solvent: CCO
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1NC(=N)N

Procedure:
9.1 ml (0.13 mol) of 65% nitric acid are added dropwise in the course of 5 minutes to a yellow suspension of 20.0 g (0.13 mol) of 2-amino-4-nitrotoluene in 50 ml of absolute ethanol. When the exothermic reaction has subsided, 8.32 g (0.198 mol) of cyanamide dissolved in 8.3 ml of water are added. The brown reaction mixture is boiled at reflux for 25 hours, cooled to 0.degree. and filtered. Washing with 4.times.100 ml of ethanol/diethyl ether (1:1) and drying yield 2-methyl-5-nitrophenyl-guanidine nitrate; m.p. 219° C.-226° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:3]=1.O[C:20]1[C:29]2[C:24](=CC=CC=2)[N:23]=[C:22]([C:30]2C=CC(F)=CC=2)[N:21]=1.S(Cl)(Cl)=O.CN(C)C=O>C(Cl)(Cl)Cl>[N:23]1[CH:24]=[CH:29][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:3]=2)=[CH:30][CH:22]=1
Reactant: Oc1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: Fc1ccc(-c2nc(Cl)c3ccccc3n2)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc(Nc3ccncc3)c3ccccc3n2)cc1

Procedure:
4-Chloro-2-(4-fluorophenyl)quinazoline: 4-hydroxy-2-(4-fluorophenyl)quinazoline, from paragraph B, 1 equivalent, was suspended in chloroform and treated with 12 equivalents of thionyl chloride in the presence of a catalytic amount of dimethyl formamide, under reflux for 4 hours. After removal of the solvents under reduced pressure a solid was obtained that was analyzed by TLC. EIMS confirmed the desired product.