Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])=[CH:9][CH:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Fc1ccccc1Oc1ccc(NCc2cccnc2)cc1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(Oc2ccccc2F)cc1

Procedure:
Using the method of Example 342 using N-(4-(2-fluorophenoxy)phenyl)pyrid-3-ylmethylamine and ethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 99:1 to 97:3 DCM/MeOH gave the title compound. Anal Calcd for C20H19FN2O3S.0.2H2O: C, 61.59; H, 5.01; N, 7.18. Found: C, 61.65; H, 4.85; N, 7.14. MS found 387.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH2:10]([Si:17]1(C2C=CC=CC=2)[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:10]([Si@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=2)=[O:24])[CH2:21][CH2:22]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Reactant: Oc1ccc(Cl)c(F)c1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2ccc(Cl)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using 4-chloro-3-fluorophenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]1([C@H:14]2[CH2:19][C@H:18]3[C@H:20]4[C@H:30]([CH2:31][CH2:32][C@:16]3([CH3:17])[C@H:15]2[OH:34])[C@:28]2([CH3:29])[C@H:23]([CH2:24][CH2:25][C@@H:26]([OH:33])[CH2:27]2)[CH2:22][CH2:21]4)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>N1C=CC=CC=1>[C:1]([O:34][C@H:15]1[C@@H:14]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:19][C@H:18]2[C@H:20]3[C@H:30]([CH2:31][CH2:32][C@:16]12[CH3:17])[C@:28]1([CH3:29])[C@H:23]([CH2:24][CH2:25][C@@H:26]([OH:33])[CH2:27]1)[CH2:22][CH2:21]3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C[C@H](O)CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@@H](N2CCCCC2)C[C@H]2[C@@H]3CC[C@H]4CC[C@@H](O)C[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 2 h

Procedure:
Acetic anhydride (5.25 ml) was added dropwise to a stirred solution of 16β-(1-piperidinyl)-5α-androstane-2β,17β-diol (14.0 g) in pyridine (280 ml) maintaining the temperature below 5° C. by means of an ice-bath. When the addition was complete, the cooling bath was removed. After 2 h, saturated sodium carbonate solution (approx. 120 ml) was added to give pH >7 and the precipitated product was extracted into dichloromethane (100 ml). The extract was washed with water (3×200 ml), dried (MgSO4) and evaporated to dryness. Crystallisation of the residue from acetone afforded 16β-(1-piperidinyl)-5α-androstane-2β,17β-diol 17-acetate (14.38 g), m.p. 239°-240° C.; [α]D +25.5° C. (c 0.53 in CHCl3).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C([O:9][C:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]3)=[N:16][N:15]2[CH:38]=1)=O)C>>[CH2:1]([NH:6][C:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:34])([F:36])[F:35])[CH2:24][CH2:25]3)=[N:16][N:15]2[CH:38]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Product: CCCCCNC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 56 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use n-pentylamine in place of isoamylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 56% yield (0.062 g). m.p. 179-180° C. 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.75-7.5 (m, 4H), 7.38-7.27 (s, 2H), 6.89 (d, J=9.6 Hz, 1H), 4.07-3.8 (m, 2H), 3.7-3.51 (m, 2H), 3.5-3.28 (m, 6H), 1.68-1.52 (m, 2H), 1.45-1.28 (m, 4H), 0.89 (t, J=2.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 162.3, 154.8, 138.2, 134.3, 134.2, 132.4, 129.5, 127.1, 126.8, 126.8, 126.2, 125.4, 121.8, 118.2, 111.9, 46.2, 41.2, 39.1, 29.4, 29.1, 22.4, 13.9. MS (ES+) m/z 489.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:15][C:3]1[C:4](=[O:14])[NH:5][C:6](=[O:13])[N:7]([CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C:2]=1[NH2:1]
Reactant: CC(C)(C)Cn1c(N)c(N=O)c(=O)[nH]c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)Cn1c(N)c(N)c(=O)[nH]c1=O

Procedure:
To a suspension of 6.0 g of XXVII in 100 ml of water was added 13.0 g of sodiumdithionite in portions. The green crystals were filtered off and washed with water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[C:21](Cl)(=O)[CH2:22][CH2:23][CH3:24].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH2:22][CH2:23][CH3:24])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: CCCC(=O)Cl
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reaction time: 4.5 h

Procedure:
A mixture of 1.5 g of 7-bromo-2-hydrazino-5-(2-pyridinyl)-3H-1,4-benzodiazepine in 45 ml of tetrahydrofuran cooled in an ice bath over a nitrogen atmosphere is added 0.57 ml of butyryl chloride dropwise over 90 sec. After stirring for 4.5 hrs, there is added an additional 0.1 ml of butyryl chloride. The resulting mixture is then stirred at ambient temperature for 18 hrs, poured into 300 ml of aqueous sodium bicarbonate and filtered. The filtrate is extracted with dichloromethane, washed with dilute brine, dried over sodium sulphate, and concentrated under reduced pressure. The resulting residue is then heated in an oil bath at 120°-125° C. for 45 min, allowed to cool, and concentrated under reduced pressure. The residue is then dissolved in dichloromethane, washed with aqueous sodium bicarbonate and dilute brine, dried over sodium sulphate, and concentrated under reduced pressure. The resulting residue is then chromatographed on 150 g of silica gel eluting with 2.5% methanol in dichloromethane. Crystallization from ethyl acetate yields 0.27 g of title product. Melting point is 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[C:4](I)[CH:3]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[CH:16]>CCN(CC)CC.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[C:4]([C:16]#[C:15][C:14]([CH3:18])([CH3:17])[CH3:13])[CH:3]=1
Reactant: OCCNc1cnc(Cl)cc1I
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1cc(Cl)ncc1NCCO
Yield: 29.1 %

Procedure:
To a solution of 2-(6-chloro-4-iodopyridin-3-ylamino)ethanol (14.5 g, 49 mmol) in Et3N (200 mL) were added 3,3-dimethyl-but-1-yne (12.0 g, 146 mol), CuI (0.9 g, 4.9 mmol) and Pd(PPh3)Cl2 (3.4 g, 4.9 mmol) under N2 atmosphere. The mixture was refluxed overnight and quenched with H2O (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and purified by chromatography on silica gel (3% ethyl acetate in petroleum ether as eluant) to afford 2-(6-chloro-4-(3,3-dimethylbut-1-ynyl)pyridin-3-ylamino)ethanol (3.6 g, 29%). 1H-NMR (CDCl3, 300 MHz) δ 7.74 (s, 1H), 7.11 (s, 1H), 4.77 (br s, 1H), 3.92-3.90 (m, 2H), 3.78-3.36 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:29])[C:21]([CH2:26][O:27][CH3:28])([CH2:23][O:24][CH3:25])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:47])[C@@H:15]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si](C(C)(C)C)(C)C)[CH2:33]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:29])[C:21]([CH2:26][O:27][CH3:28])([CH2:23][O:24][CH3:25])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:47])[C@@H:15]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([OH:39])[CH2:33]2)=[CH:10]1
Reactant: COCC(C)(COC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCC(C)(COC)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 78.2 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 200 mg of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-(2,2-bis[methoxymethyl]propionyloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 160, above] and 4.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 105 mg of the title compound as colorless needle-like crystals, melting at between 122° and 123° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[N:14]=[C:15]([NH:18][C:19](=[O:22])[CH2:20][Cl:21])[S:16][CH:17]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[C:29]1([CH:35]([O:42][C:43]([C:45]2[N:50]3[C:51](=[O:54])[C@@H:52]([NH2:53])[C@H:49]3[S:48][CH2:47][C:46]=2[CH:55]([S:57][C:58]2[NH:62][N:61]=[N:60][N:59]=2)[CH3:56])=[O:44])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1>C(Cl)Cl>[C:29]1([CH:35]([O:42][C:43]([C:45]2[N:50]3[C:51](=[O:54])[C@@H:52]([NH:53][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]4[N:14]=[C:15]([NH:18][C:19](=[O:22])[CH2:20][Cl:21])[S:16][CH:17]=4)[C@H:49]3[S:48][CH2:47][C:46]=2[CH:55]([S:57][C:58]2[NH:62][N:61]=[N:60][N:59]=2)[CH3:56])=[O:44])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1csc(NC(=O)CCl)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(NC(=O)OC(C)(C)C)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a suspension of 349 mg of α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl]acetic acid in 5 ml of methylene chloride is added 249 mg of phosphorous pentachloride, and the mixture is stirred at room temperature. The mixture is added dropwise under stirring to the solution of 494 mg of 7β-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester dissolved in 5 ml of methylene chloride, followed by the addition of 474 mg of pyridine. After that, the stirring is continued for further 1 hour at room temperature. The reaction solution is washed with 0.5N hydrochloric acid and then with water, and dried. The oily product obtained by the distillation of the solvent is purified by a column chromatography packed with silica gel. The procedure gives 513 mg of 7β-{α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl]acetamido}-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CN(C1C=CC=CN=1)C>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: C1CCNC1
Reactant: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCBr
Agent: CN(C)c1ccccn1
Solvent: c1ccccc1
Product: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCN1CCCC1

Procedure:
0.10 g (0.23 mmol) of N-{3-(3,4-dimethylphenyl)propyl}-4-(2-bromoethoxy)-3-methoxyphenylacetamide obtained in Step 5 of Example 3, 0.16 g (2.3 mmol) of pyrrolidine and a catalytic amount of dimethylaminopyridine were dissolved in 10 ml of benzene, and the mixture was refluxed for 5 hours. After removing the solvent under a reduced pressure, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate:hexane=1:1) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:10]([Cl:9])(=[O:12])=[O:11]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(Br)cc1
Product: Cc1ccc(Br)c(S(=O)(=O)Cl)c1
Temperature: 0 °C

Procedure:
40 g of 4-bromotoluene are slowly introduced into 250 ml of chlorosulfonic acid at −10° C. with stirring. The mixture is stirred at this temperature for 30 minutes, allowed to warm to 0° C. and poured onto excess ice. The product is filtered off with suction and washed with a little water. It is dried over P4O10 in vacuo and 63 g of a colorless solid are obtained, which is directly reacted further.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[N:34]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:38]([C:35]2[CH:36]=[CH:37][N:33]([CH3:32])[N:34]=2)=[O:39])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: Cn1ccc(C(=O)Cl)n1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccn(C)n4)cc3F)ccnc2cc1OCCCN1CCOCC1

Procedure:
Q3 was prepared from 3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]aniline and 1-methyl-1H-pyrazole-3-carbonyl chloride following the general procedure reported in Preparative Example 1 Step 3. 1H NMR (400 MHz, d4-MeOD, 300K) δ 2.10 (m, 2H), 2.52 (m, 4H), 2.62 (t, J=7.5 Hz, 2H), 3.70 (t, J=4.7 Hz, 4H), 3.99 (s, 3H), 4.00 (s, 3H), 4.22 (t, J=6.2 Hz, 2H), 6.49 (d, J=5.4 Hz, 1H), 6.83 (d, J=2.3 Hz, 1H), 7.33 (m, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.94 (dd, J=12.7 Hz, J=2.4 Hz, 1H), 8.40 (d, J=5.4 Hz, 1H). MS (ES) C28H30FN5O5 requires: 535. Found: 536 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[O:15][CH3:16].Cl>CO.[Pd]>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[NH2:12]
Reactant: COc1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1c(N)cc(C(F)(F)F)cc1Cl
Yield: 101.1 %

Procedure:
1-Chloro-2-methoxy-3-nitro-5-trifluoromethylbenzene (3.46 g, 13.5 mmol) was dissolved in MeOH (74 mL). Hydrochloric acid (2M, 13 mL, 26 mmol) and Pd/C (10%, 0.44 g) was added. Hydrogenation at atmospheric pressure and at room temperature for 1 h 30 min, filtration and evaporation of the solvent gave a crude product. Purification by flash chromatography (SiO2, CH2Cl2 -hexane 1:2 followed by EtOAc-NH3 100:0.1) yielded the title compound (3.08 g) as an oil. 1H NMR (CDCl3): 7.00 (J 1.8 Hz, 1H), 6.85 (d, J=1.95 Hz, 1H), 4.11 (br s, 2H), 3.87 (s, 3H). MS (EI, 70 eV): m/z (rel. int.) 227/225 (M+, 17/58).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[N:23]([CH3:24])[N:22]=[N:21][N:20]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[N:23]([CH3:24])[N:22]=[N:21][N:20]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Reactant: Cn1nnnc1Br
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nnnn3C)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 5-bromo-1-methyl-1H-tetrazole (Can. J. Chem. 1971, 49, 2139).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[CH2:12]1)C1C=CC=CC=1.Br>C(O)(=O)C>[F:27][C:25]([F:26])([F:28])[C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:16]2[CH2:17][CH2:18][C:13]3([CH:11]([NH2:10])[CH2:12]3)[CH2:14][CH2:15]2)[N:24]=1
Reactant: O=C(NC1CC12CCN(c1nccc(C(F)(F)F)n1)CC2)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NC1CC12CCN(c1nccc(C(F)(F)F)n1)CC2
Yield: 1001.4 %

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.5.). Starting with 0.86 g (2.13 mmol) of benzyl[6-(4-trifluoromethylpyrimidin-2-yl)-6-azaspiro[2.5]oct-1-yl]carbamate obtained in the preceding step and 3.74 mL (21.33 mmol) of a solution of 35% hydrobromic acid in acetic acid, and after basic extraction and uptake in diethyl ether, 0.32 g of product is obtained in the form of a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@:4]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH2:25][OH:26])=[O:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1.ClCCl>[C:27]([O:26][CH2:25][C@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:18]([C@@:4]1([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])=[O:19])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COC1=CCc2ccccc2[C@]1(CCC(C)C)C(=O)N1CCC[C@@H]1CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1=CCc2ccccc2[C@]1(CCC(C)C)C(=O)N1CCC[C@@H]1COC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 171B (54 mg, 0.15 mmol) in anhydrous pyridine (0.5 mL) was added acetic anhydride (50 μL, 0.53 mmol). The resulting mixture was stirred under a N2 atmosphere at r.t. for 16 h, diluted with dichloromethane (10 mL), and extracted with 0.2 N HCl (2×10 mL). The organic layer was dried over Na2SO4, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 25-50% ethyl acetate in hexane. The title compound was obtained as a colorless solid (50 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 0.51 (m, 1 H), 0.71 (d, J=6.62 Hz, 3 H), 0.77 (d, J=6.62 Hz, 3 H), 0.94 (m, 2 H), 1.39 (m, 2 H), 1.64 (m, 3 H), 2.04 (m, 1 H), 2.04 (s, 3 H), 2.26 (m, 1 H), 2.49 (m, 1 H), 3.16 (m, 1 H), 3.47 (m, 1 H), 3.59 (s, 3 H), 4.11 (m, 1 H), 4.25 (m, 1 H), 4.41 (m, 1 H), 4.97 (m, 1 H), 7.14 (m, 4 H).
Reaction SMILES: [N:1]1([N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20](O)=[O:21])=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH2:27]([NH2:30])[C:28]#[CH:29]>>[CH2:27]([NH:30][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[NH:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([CH:7]=[N:6][N:1]3[CH:2]=[CH:3][CH:4]=[CH:5]3)=[N:9][NH:10]2)=[CH:15][CH:14]=1)[C:28]#[CH:29]
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Nn3cccc3)n[nH]c2c1
Reactant: C#CCN
Product: C#CCNC(=O)c1ccccc1Nc1ccc2c(C=Nn3cccc3)n[nH]c2c1

Procedure:
Prepared in a similar manner to that described for Example 6 above, except using 2-[3-(Pyrrol-1-yliminomethyl)-1H-indazol-6-ylamino]-benzoic acid and propargylamine. 1H NMR (DMSO-d6) δ 13.30 (1H, s), 9.82 (1H, s), 9.04 (1H, t, J=5.6 Hz), 8.98 (1H, s), 8.19 (1H, d, J=8.6 Hz), 7.69 (1H, d, J=7.9 Hz), 7.45(4H, m), 7.31 (1H, s), 7.08 (1H, d, J=8.6 Hz), 6.91 (1H, t, J=7.6 Hz), 6.21 (2H, s), 4.05 (2H, s), 3.13 (1H, s). Anal. Calcd for C22H18N6O. 0.40H2O. 0.05 Hexanes: C, 67.97; H, 5.01; N, 21.33. Found: C, 67.91; H, 4.78; N, 21.00.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[S:23])[CH3:20]>O1CCCC1>[CH2:19]([NH:21][C:22]([NH:11][CH:7]1[C:4]2[CH:5]=[CH:6][S:2][C:3]=2[CH2:10][CH2:9][CH2:8]1)=[S:23])[CH3:20]
Reactant: NC1CCCc2sccc21
Reactant: CCN=C=S
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=S)NC1CCCc2sccc21
Temperature: 50 °C
Reaction time: 0.38 h

Procedure:
A sample of 9.48 grams of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is stirred in 100 ml. of dry tetrahydrofuran, and 6.06 grams of triethylamine is added. After stirring for 15 to 30 minutes, 5.23 grams of ethyl isothiocyanate in 20 ml. of dry tetrahydrofuran is added dropwise, and the mixture is heated for 2 hours at 50° C. The mixture is cooled and filtered, and the filter cake is washed with hexane. The filtrate is evaporated to dryness and poured on ice. The oil is extracted with ether, and the extract is washed with 1N sulfuric acid, water, and saturated sodium bicarbonate solution. The ether extract is dried and evaporated to dryness to afford an oil. This oil crystallizes in ether to afford 1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)thiourea, melting point 106° C. to 112° C.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].[Mn]([O-])(=O)(=O)=O.[K+].C[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH2:5]([O:4][C:2]([NH:1][C:18]1[CH:17]=[C:16]([NH:1][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:15]=[CH:14][C:19]=1[CH3:20])=[O:3])[CH3:6]
Reactant: CCOC(N)=O
Reactant: Cc1ccccc1C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CCOC(=O)Nc1ccc(C)c(NC(=O)OCC)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
10 g of the urethane which had previously been treated in this way were dissolved in 60 g o-xylene. The solution is heated to 80° C. and mixed with 2 g of a 2%, by weight, aqueous potassium permanganate solution. The mixture was stirred intensely for 30 minutes at 80° C. The hot organic phase was then separated from the solid and aqueous constituents. The organic phase was concentrated by distilling off a proportion of the xylene to half of its original volume, and the purified 2,4-bis-(ethoxycarbonylamino)-toluene was obtained in a virtually quantitative yield from the concentrated solution by crystallization.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[OH:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][CH:10]=1.NC1C=CC=CC=1.Cl>N1C=CC=CC=1>[CH:11]1[C:12](/[CH:3]=[CH:2]/[C:1]([OH:7])=[O:6])=[CH:15][CH:16]=[C:9]([OH:8])[CH:10]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: Nc1ccccc1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 7.5 h
Yield: 80 %

Procedure:
Malonic acid, 813 g, was added to p-hydroxy benzaldehyde, 472 g, in pyridine, 957 ml. The mixture was heated to 65° C. and aniline, 28 ml, was added. The reaction was stirred at 65° C. for 7.5 hours and then cooled to room temperature. HCl, 2.75 L, 2N HCl, was then added dropwise while the reaction stirred A creamy precipitate formed. The reaction was stirred for an additional 10 minutes. The precipitate was collected by filtration and dried under reduced pressure. The solid was identified as coumaric acid by IR spectroscopy. The yield was ≥80%.