Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[F:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:7]=[CH:6][C:5]=1[F:11]
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1cc(N)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N=Cc2cccc(Br)c2)ccc1F
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture solution of 5-amino-2-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+] 336.0 & 338.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O>[CH2:22]([O:21][C:19]([CH2:18][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:20])[CH3:23]
Reactant: NC(=O)c1ccccc1N
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)CNc1ccccc1C(N)=O
Temperature: 160 °C
Yield: 23.3 %

Procedure:
To 2 g of ortho-aminobenzamide were added 4.04 g (2 equivalents) of potassium carbonate, 4.94 g (2 equivalents) of ethyl bromoacetate, and the mixture was stirred under heating at 160° C. for 3 hours. After cooling to room temperature, water was added and the mixture extracted with ethyl acetate. After washing with aqueous sodium chloride, the mixture was dried over anhydrous magnesium sulfate, followed by evaporation of the solvent. The residue was developed with hexaneethyl acetate (1:2) by silica gel column chromatography to obtain 760 mg of the desired compound (yield 23.3%).
Reaction SMILES: [C:1]([OH:18])(=[O:17])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C1(C)C(C)=CC=CC=1>[CH2:19]([O:14][C:13](=[O:15])[C:12]1[C:8](=[CH:7][C:3](=[C:2]([CH:16]=1)[C:1]([O:18][CH2:9][CH2:8][CH2:7][CH2:3][CH2:2][CH2:16][CH2:12][CH3:13])=[O:17])[C:4]([O:6][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:5])[C:9]([O:11][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:10])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Reactant: CCCCCCCCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1C
Product: CCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCC)c(C(=O)OCCCCCCCC)cc1C(=O)OCCCCCCCC
Yield: 209 %

Procedure:
To a 2-liter four necked flask equipped with Dean Stark, 218 g of anhydrous pyromellitic acid, 650 g of n-octanol, 0.2 g of titanium tetraisopropoxide and 300 ml of xylene were added and reacted with agitation at 160 degrees C. for 4 hours under nitrogen stream while distilling water. Subsequently, washing by saturated saline and washing by 0.1 N aqueous sodium hydroxide were respectively conducted three times, followed by being dried by anhydrous magnesium sulfate. After magnesium sulfate was filtered, unreacted alcohol was distilled under diminished pressure to obtain 630 g of pyromellitic acid tetraoctyl ester as a residue. The obtained compound, regarded as Comparative 2-3, was similarly measured with respect to the properties.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH:18]=[CH:19][C:20]=1[F:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH:28][C:26](=[NH:27])[CH2:25][O:24][CH2:23][CH2:22][C:17]1[CH:18]=[CH:19][C:20]([F:21])=[C:15]([Cl:14])[CH:16]=1)=[O:6]
Reactant: N=C(N)COCCc1ccc(F)c(Cl)c1
Reactant: CCc1cnc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(Cl)c(C(=O)NC(=N)COCCc2ccc(F)c(Cl)c2)c1

Procedure:
In analogy to the procedure described in example 78.3, 2-chloro-5-ethyl-nicotinic acid (example 124.1) was reacted with 2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 82.2) in the presence of TBTU and DIPEA to give 2-chloro-N-{2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-1-imino-ethyl}-5-ethyl-nicotinamide as yellow oil. MS: m/e=398.1 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(N(CC)CC)C>CCCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:21])[CH2:20][C:30]([C:25]3[CH:26]=[C:27]([Cl:29])[CH:28]=[C:23]([Cl:22])[CH:24]=3)([OH:35])[C:31]([F:34])([F:33])[F:32])=[CH:17][CH:18]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(C2(F)CN(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)CC(O)(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Temperature: 60 °C

Procedure:
In a clean and dry seal tube, to a stirred solution of 3-(4-acetyl-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (4 g, 13.652 mmol, 1eq.) in heptane (40 mL) was added 1-(3,5-dichlorophenyl)-2,2,2-trifluro-ethanone (6.60 gm, 27.304 mmol, 2eq.) followed by addition of triethyl amine (TEA, 3.80 ml, 27.304 mmol, 2eq.) at room temperature. Resulting reaction mixture was heated at 60° C. for 16 hours. After maximum consumption of starting material, reaction mixture was cooled to room temperature, solid precipitated out. Solid was filtered over Buchner funnel and washed with heptane (2×30 mL) and n-Pentane (70 mL) and dried under reduced pressure to get product as white solid. Yield: −5.0 g (68.31%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.68 (d, J=17.36 Hz, 1H), 3.85 (d, J=17.44 Hz, 1H), 4.17-4.24 (m, 2H), 4.39-4.47 (m, 2H), 5.69 (s, 1H), 7.33-7.35 (m, 1H), 7.48 (d, J=1.16 Hz, 2H), 7.62 (d, J=8.44 Hz, 2H), 7.98 (d, J=8.28 Hz, 2H). LC-MS (m/z): =534.0 (M−H).
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Cl[CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>>[O:20]=[S:19]1(=[O:21])[CH2:18][CH2:17][CH2:16][N:1]1[C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)(C)N)cc1
Reactant: O=S(=O)(Cl)CCCCl
Product: COC(=O)c1ccc(C(C)(C)N2CCCS2(=O)=O)cc1

Procedure:
Using methyl 4-(1-amino-1-methylethyl)benzoate (570 mg) and 3-chloropropane-1-sulfonyl chloride (0.47 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (862 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[O:14]=[C:6]1[N:5]([CH2:4][CH2:3][NH:2][S:23]([CH3:22])(=[O:25])=[O:24])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1c(=O)[nH]c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.1 %

Procedure:
To a solution of 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (2.8 g, 13 mmoles) in THF (30 ml) and triethyl amine (5.5 ml, 39 mmoles) was added methanesulfonyl chloride (1.12 ml, 14 mmoles) and the reaction mixture was stirred for 2 hours at room temperature. The organic solvent was evaporated and the residue was partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous Na2CO3 solution and taken to dryness. The crude residue was purified by flash chromatography (CH2Cl2-methanol 96-4) to give 0.5 g of the title compound as a white solid. M.p. 162-170° C.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:18])[CH:11]=[C:12]2[Cl:17])=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[C:3]([C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([CH3:19])[CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:18])[CH:11]=[C:12]2[Cl:17])=[N:7]1)#[N:4]
Reactant: COc1c2c(Cl)cc(Cl)cc2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: COc1c2c(Cl)cc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (30 mg, described in Example 116) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (42 mg, 83%). MS (ES): M/Z [M+H]=503. 1H NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 4.12 (s, 3H), 4.94 (d, J=6.5 Hz, 2H), 7.17 (d, J=1.2 Hz, 1H), 7.62 (d, J=1.1 Hz, 1H), 7.86-7.91 (m, 2H), 7.93-7.99 (m, 2H) and 9.03 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][C:11]([S:14]([C:17]1[CH:34]=[CH:33][C:20]2[N:21]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[C:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:23][C:19]=2[CH:18]=1)(=[O:16])=[O:15])([CH3:13])[CH3:12])(=O)=O>CN(C=O)C>[N:1]([CH2:13][C:11]([S:14]([C:17]1[CH:34]=[CH:33][C:20]2[N:21]([CH2:29][CH:30]3[CH2:31][CH2:32]3)[C:22]([CH2:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:23][C:19]=2[CH:18]=1)(=[O:16])=[O:15])([CH3:10])[CH3:12])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)COS(C)(=O)=O)ccc2n1CC1CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CN=[N+]=[N-])ccc2n1CC1CC1
Temperature: 160 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of sodium azide (176 mg, 2.70 mmol) in N,N′-dimethylformamide (5 mL) was added 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropyl methanesulfonate (Step I, 411 mg, 0.90 mmol) in N,N′-dimethylformamide (3 mL) at room temperature. The mixture was stirred at 160° C. for 24 h. The mixture was washed with ethyl acetate (20 mL×3) and water (30 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:2 as eluent) to afford the title compound (265 mg) as a white amorphous.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[CH:32]=[CH:31][C:30]([S:33][C:34]2[N:35]=[CH:36][N:37]3[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=23)=[CH:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:40]3[S:39][C:38]4=[C:34]([S:33][C:30]5[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=5)[N:35]=[CH:36][N:37]4[CH:41]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(Sc3ccncc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(Sc5ccncc5)c4s3)[C@H](C)[C@H]12
Yield: 4.9 %

Procedure:
The procedure of Example 1a) was repeated, except that 1.18 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.78 g of 7-(pyridin-4-yl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 93.1 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:60]2[CH2:61][CH2:62][N:57]([C:55]([O:54][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:56])[CH2:58][CH2:59]2)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:44])[CH3:45])=[O:42]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCN(C(=O)OC(C)(C)C)CC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 4.9 %

Procedure:
With 2.00 g of the compound obtained in Example 219 and 3.3 g of piperazine-1-carboxylic acid tert-butyl ester as starting materials, 120 mg of the title compound (colorless oil) was obtained by a similar procedure to Example 227.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
In a round-bottomed flask 6-bromo-1H-indazole (0.70 g, 3.55 mmol) was dissolved in DMF (7.5 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 172 mg, 4.3 mmol) was added). The reaction mixture was warmed to room temperature and stirred for 30 min then cooled back to 0° C. and SEM-Cl (0.76 ml, 4.28 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was warmed to room temperature. After 1.5 h the reaction was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/Hexanes (gradient 0-10% EtOAc) to give 802 mg (69%) of 6-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].Br[CH2:12][CH2:13][O:14][CH3:15]>C(O)C>[CH3:15][O:14][CH2:13][CH2:12][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccccc1S
Reactant: COCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCSc1ccccc1N
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 2-aminothiophenol (93%, 123 g, 0.910 mol) and sodium hydroxide (40.2 g, 1.00 mol) in 90% aqueous ethanol (637 ml) was added dropwise 2-bromoethylmethylether (127 g, 0.910 mol) at room temperature. When the addition was complete, the reaction mixture was refluxed for 2 hours, cooled to room temperature, and then concentrated in vacuo. The resulting residue was diluted with water (1400 ml) and extracted with methylene chloride (3×500 ml). The extracts were washed with water (2×500 ml) and brine (500 ml), dried with (MgSO4), filtered and concentrated to give a dark oil. Distillation of the crude product gave 2-(2-methoxyethylthio)benzenamine (148 g, 89%) as a light yellow oil; bp 90°-103° (0.1 mm).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]3)=[N:5][N:4]=[C:3]1[CH2:18][CH2:19][CH2:20][CH:21]=O.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:39]=[CH:38][C:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37][C:31]=3[CH:30]=2)[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:39]=[CH:38][C:32]3[CH2:33][CH2:34][N:35]([CH2:21][CH2:20][CH2:19][CH2:18][C:3]4[N:2]([CH3:1])[C:6]([C:7]5[CH:8]=[C:9]6[C:14](=[CH:15][CH:16]=5)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]6)=[N:5][N:4]=4)[CH2:36][CH2:37][C:31]=3[CH:30]=2)[CH:25]=1
Reactant: Cc1cc(-c2ccc3c(c2)CCNCC3)no1
Reactant: Cc1ccc2cc(-c3nnc(CCCC=O)n3C)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2cc(-c3nnc(CCCCN4CCc5ccc(-c6cc(C)on6)cc5CC4)n3C)ccc2n1
Yield: 21.4 %

Procedure:
4-[4-Methyl-5-(2-methyl-quinolin-6-yl)-4H-[1,2,4]triazol-3-yl]-butyraldehyde (76 mg, 0.25 mmol) and 7-(5-Methyl-isoxazol-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (55 mg, 0.24 mmol) were stirred at room temperature in dichloromethane (5 ml) for 30 min. Sodium triacetoxyborohydride (55 mg, 0.26 mmol) was then added and the mixture stirred over the weekend. The mixture was diluted with dichloromethane (50 ml) and washed with saturated sodium bicarbonate solution (30 ml). The aqueous was extracted with further dichloromethane (50 ml) and the combined organic portions were dried (Na2SO4), filtered and evaporated to give the desired compound as an off-white solid (26 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.ClCCl.CO.N>>[N:19]1([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][N:12]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 2.3.f. from [5-(4-chlorophenyl)pyridin-2-yl]propynoic acid and 4-piperidin-1-ylmethylphenylamine. Yield: 0.2 g (48% of theory); C26H24ClN3O (M=429.95); calc.: molecular ion peak (M+H)+: 430/432; found: molecular ion peak (M+H)+: 430/432; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (90:10:0.1)).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:8][C:9]1([C:32]([O:34]CC)=O)[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:10]12.[Cl-].[NH4+].O>C1COCC1>[F:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:8][C:9]1([C:32](=[O:34])[CH3:1])[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:10]12
Reactant: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(C)=O)ccc1-c1cnc(C)o1

Procedure:
Methylmagnesium bromide (12% THF solution, 13 mL) was added to a mixture of ethyl 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.60 g) in THF (16 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, and methylmagnesium bromide (12% THF solution, 13 mL) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and further recrystallized from ethyl acetate/hexane to give the title compound (121 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6].Cl>[Fe].CO>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([N:2]([CH3:14])[CH3:1])[C:4]=1[C:5]#[N:6]
Reactant: CN(C)c1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CN(C)c1cccc(N)c1C#N
Reaction time: 0.5 h

Procedure:
To a suspension of 5.7 g. of 2-dimethylamino-6-nitrobenzonitrile in 20 ml. of methanol and 17 ml. of concentrated hydrochloric acid is added 5.3 g. of iron powder in portions. The mixture is stirred for 1/2 hour, diluted with 200 ml. of water and extracted with methylene chloride which is dried and evaporated in vacuo to yield crude 2-amino-6-dimethylaminobenzonitrile.
Reaction SMILES: [CH:1]1([N:5]2[C:10]([NH2:11])=[C:9]([NH2:12])[C:8](=[O:13])[NH:7][C:6]2=[O:14])[CH2:4][CH2:3][CH2:2]1.[C:15](O)(=O)[CH3:16]>>[CH:1]1([N:5]2[C:10]3[N:11]=[C:15]([CH3:16])[NH:12][C:9]=3[C:8](=[O:13])[NH:7][C:6]2=[O:14])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)O
Reactant: Nc1c(N)n(C2CCC2)c(=O)[nH]c1=O
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C1CCC1

Procedure:
A solution of 2.2 g of 1-cyclobutyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (X) in 10 ml of acetic acid was refluxed for 2 hours. The solution was evaporated. The received oil was refluxed in 30 ml of 5N NaOH for 1 hour and then neutralized with 5 N HCl. The crystals were filtered off and recrystallized from 100 ml ethanol. Yield 0.4 g (18%) (XXXVII) NMR (see Table I).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:12][C:13]1[CH:14]=[N:15][N:16]([CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH:17]=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl.CCOC(C)=O>[CH3:22][C:19]([CH3:23])([CH2:20][O:21][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[CH2:18][N:16]1[CH:17]=[C:13]([I:12])[CH:14]=[N:15]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)Cn1cc(I)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(COC1CCCCO1)Cn1cc(I)cn1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
p-Toluenesulfonic acid (44 mg, 0.26 mmol) was added to a stirring solution of 3-(4-iodopyrazol-1-yl)-2,2-dimethyl-propan-1-ol (Compound 47E, 500 mg, 1.79 mmol) in DCM (2.58 mL). The mixture was stirred under argon, chilled in an ice-bath, then dihydropyran (0.261 mL, 2.86 mmol) was added, stirred and gradually warmed to rt over 16 hrs. The reaction mixture was diluted with EtOAc and washed with brine (2×), dried over sodium sulfate, filtered and concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→10% EtOAc/Heptanes] to afford 597 mg of the title compound (92%). 1H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 7.48 (s, 1H), 4.57 (t, J=3.5 Hz, 1H), 4.04-4.12 (m, 2H), 3.86 (d, J=3.0 Hz, 1H), 3.48-3.56 (m, 1H), 3.45 (d, J=9.3 Hz, 1H), 3.03 (d, J=9.6 Hz, 1H), 1.81-1.91 (m, 1H), 1.67-1.78 (m, 1H), 1.51-1.66 (m, 4H), 0.93 (d, J=4.8 Hz, 6H).