Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].Cl.[NH2:35][CH:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:35][CH:36]4[CH2:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH2:37]4)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:19])=[O:20])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: NC1Cc2ccccc2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC2Cc3ccccc3C2)cc1OC
Yield: 70.4 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 0.8 g of the compound obtained in EXAMPLE 13, 0.35 g of 2-aminoindane hydrochloride, 0.8 g of BOP, 2 ml of DIPEA and 20 ml of DCM. It is chromatographed on silica using a DCM/AcOEt mixture (96/4; v/v) as the eluent to give 0.7 g of the expected product in the form of white crystals. M.p.=160° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11]Br)[CH:5]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][O:17][C:14](=[O:16])[CH3:15])[CH:5]=1
Reactant: COC(=O)c1cc(C)cc(CBr)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(C)cc(COC(C)=O)c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
In a 5 liter flask were combined 507 g (2.09 mole) of methyl-3-bromomethyl-5-methylbenzoate with 615 g (6.3 mole) of potassium acetate in 2850 ml of glacial acetic acid and refluxed for 3 hours. The contents of the flask were then cooled down to room temperature and divided in 3 equal portions for work up. Each portion was poured into 2 liter of water and extracted with ethyl ether (3×300 ml). The combined organic layers were washed with water (3×600 ml) and then with 2% aqueous sodium hydroxide (5×200 ml) and then dried over sodium sulfate. The solvent was then eliminated in the rotavap to give 420.8 g (90% yield) of crude product, used as such in the next step.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CCCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccccc32)cc1
Yield: 96.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and (4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.54 g) as starting materials, N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.81 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[S:17][C:10]=2[NH:11][C:12](=O)[CH:13]([CH3:15])[N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[S:17][C:10]=2[NH:11][C:12](=[S:41])[CH:13]([CH3:15])[N:14]=1
Reactant: CC(C)Cc1ccc(CCc2cc3c(s2)NC(=O)C(C)N=C3c2ccccc2Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(CCc2cc3c(s2)NC(=S)C(C)N=C3c2ccccc2Cl)cc1
Yield: 99.9 %

Procedure:
A suspension of 2 g of 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-3-methyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 188°-191° C. and 1.04 g of Lawesson reagent in 37 ml of toluene is stirred at 40°-45° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 1.2 g of 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-3-methyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:17](=O)[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(O)(O)(=O)=O.[CH3:25][O:26][C:27](=[NH:29])[NH2:28].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[NH:29][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:28]=1
Reactant: COC(=N)N
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A reaction mixture containing 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, ethyl ester (2.62 g, 10.0 mmole), 2-methylpseudourea sulfate (1.72 g, 10.0 mmole), and sodium bicarbonate (2.52 g, 30.0 mmole) in dimethylformamide (10 ml) was heated at 65°-70° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and filtered. The filtrate was washed with water and brine, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a yellow oil which was purified by flash chromatography (5% ethyl acetate in dichloromethane). The resulting foam was crystallized from isopropyl ether/hexanes to provide 2.41 g of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester as a colorless crystalline product; melting point 103.5°-105° C. TLC (silica gel; ethyl acetate: hexanes 50:50) Rf =0.31
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.[ClH:31].O1CCOCC1>C(Cl)Cl>[ClH:31].[F:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(S(C)(=O)=O)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
tert-Butyl 4-((1R,2R)-2-(((2-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step C product, 1.13 g, 2.56 mmol) was dissolved in DCM (20 ml) and HCl in dioxane (4 M solution, 9.60 ml, 38.4 mmol) was added. The mixture was stirred at RT for 1 h. The solvents were evaporated to afford 0.97 g of the desired product (100%) which will be used without further purification. LC/MS (m/z): 378 (M+H)+.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21](/[C:24](/[CH3:31])=[CH:25]/[C:26](OCC)=[O:27])=[CH:20][CH:19]=2)[CH:14]=[C:15]([Br:17])[CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[CH:20][C:21](/[C:24](/[CH3:31])=[CH:25]/[CH2:26][OH:27])=[CH:22][CH:23]=2)[CH:14]=[C:15]([Br:17])[CH:16]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2cc(Br)cc(Br)c2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2cc(Br)cc(Br)c2)cc1

Procedure:
The colourless gum (E)-3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-enoate as described for example 52b, with the purification of the product being carried out by preparative HPLC.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3].[CH3:16][O:17][C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)[N:19]=1.C1CCN2C(=NCCC2)CC1>>[CH3:14][O:13][N:12]=[C:11]([Cl:15])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([NH:1][C:26]([NH:25][C:20]1[N:19]=[C:18]([O:17][CH3:16])[N:23]=[C:22]([CH3:24])[N:21]=1)=[O:27])(=[O:3])=[O:4]
Reactant: CON=C(Cl)c1ccccc1S(N)(=O)=O
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Product: CON=C(Cl)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Yield: 67.4 %

Procedure:
By the procedure of Example 5, 0.4 g of the product of Example 4 was reacted with 0.46 g of phenyl (4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate and 0.25 g of DBU. The resulting suspension was acidified, without prior filtration, with concentrated hydrochloric acid and filtered. The residue was washed with excess water and suction-dried to yield 0.45 g of the subject compound, m.p. 182° to 184° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]1[NH:56][N:57]=[C:58]([C:60](O)=[O:61])[CH:59]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:58]2[N:57]=[N:56][NH:55][CH:59]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1cn[nH]n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2c[nH]nn2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 48 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2H-1,2,3-triazole-4-carboxylic acid as starting materials in 48% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.41 (m, 2H), 9.15 (s, 1H), 8.32 (m, 2H), 8.21 (m, 2H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.52 (m, 2H), 3.19 (m, 2H), 2.99 (m, 4H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C27H28ClN10O2 (M+H)+: m/z=559.2.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([CH:38]=O)[CH:32]=3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[NH2:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1.C(O)(=O)C>ClC(Cl)C.ClCCl>[C:15]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([CH2:38][NH:40][CH2:41][CH2:42][CH2:43][N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH:32]=3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-c3ccc(F)c(C=O)c3)ccc21
Reactant: NCCCN1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(-c3ccc(F)c(CNCCCN4CCCC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Sodium triacetoxyborohydride (190 mg, 0.88 mmol) was added to a mixture of 5-(4-fluoro-3-formylphenyl)-indazole-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol) and N-(3-aminopropyl)pyrrolidine (74 mg, 0.59 mmol) and acetic acid (105 mg, 1.8 mmol) in dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane and washed with 1 M sodium carbonate solution. The layers were separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 130 mg of product. LC/MS: Retention time, 1.98 min; (M+H)=453.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([Br:12])=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH3:13]>C(O)C(C)C>[CH3:1][N:2]1[C:6]2[C:7]([Br:12])=[C:8]([NH:11][C:1]3[NH:13][CH2:5][CH2:6][N:2]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: N
Reactant: Cn1cnc2ccc(N)c(Br)c21
Solvent: CC(C)CO
Product: Cn1cnc2ccc(NC3=NCCN3)c(Br)c21
Yield: 93 %

Procedure:
A solution of 3-methyl-4-bromo-5-aminobenzimidazole (0.31 g, 1.4 mmol) and ISA (0.6 g, 4.5 mmol) in 10 ml of isobutanol was stirred at reflux for 12 h. Oily residue obtained was subjected to column chromatography (NH3 sat'd 20% isopropanol/EtOAc) to yield 0.39 g (1.3 mmol, 93%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.50 g (68%) of the product as a white solid: mp 209-210° C.; Anal. Calc. for C11H12N5Br.2.0C4H4O4. requires C, 43.36; H, 3.83; N, 13.31. Found: C, 43.66; H, 3.84; N, 13.10.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:6]=1/[CH:7]=[CH:8]/[C:9](O)=[O:10].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[CH3:3][O:4][C:5]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:6]=1/[CH:7]=[CH:8]/[C:9]([Cl:23])=[O:10]
Reactant: COc1ccc(/C=C/C(=O)O)c(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve trans-2,3,4-Trimethoxycinnamic acid (50) (200 mg, 0.84 mmol) in anhydrous DCM (4.4 mL) at it and add anhydrous DMF (3 drops, cat. amount). Then add slowly oxalyl chloride (96 μL, 1.09 mmol) stir the turbid mixture for additional 2 h at rt. Remove solvent and dry the residue in oil pump vacuum to obtain trans-2,3,4-Trimethoxycinnamic acid chloride (51) (ca. 0.84 mmol) as an yellow solid. Dissolve acid chloride (51) (108 mg, 0.42 mmol) in anhydrous DCM (4.0 mL) and add it to an ice cooled solution of Methyl 3-amino-4-methylbenzoate (52) (69 mg, 0.42 mmol) in anhydrous DCM (2.0 mL) and anhydrous pyridine (1.2 mL). Stir the resulting reaction mixture at rt overnight. Pour the reaction mixture into ice cooled 1M aqu. HCl, extract with EtOAc (3×), wash the combined organic layer with brine and dry it with Na2SO4. Purify the crude product by filtration through a short pad of silica gel with EtOAc and remove solvent to obtain 4-Methyl-3-[3-(2,3,4-trimethoxy-phenyl)-acryloylamino]-benzoic acid methyl ester (53) (99 mg, 61%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): 2.35 (s, 3H); 3.87 (s, 3H); 3.88 (s, 6H); 3.91 (br.s, 3H); 6.59 (d, 1H, J=15.6 Hz); 6.68 (d, 1H, J=8.6 Hz); 7.08 (br.s, 1H); 7.20-7.29 (m, 2H); 7.77 (br.d, 1H, J=8.6 Hz); 7.90 (d, 1H, J=15.6 Hz); 8.55 (br.s 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]([NH2:29])(=[O:28])[CH:26]=[CH2:27]>CN(C)C=O>[C:25]([CH2:26][CH2:27][N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:20])[CH2:15][CH2:16]1)(=[O:28])[NH2:29]
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: C=CC(N)=O
Solvent: CN(C)C=O
Product: NC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 140 °C
Yield: 49.7 %

Procedure:
A mixture of 3.31 g (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid and 4.2 g (0.058 mole) of acrylamide in 50 ml of dimethylformamide is heated at 140° C. for 6 hours. The suspension is concentrated under a high vacuum and the residue is stirred with water and recrystallized from glycol monomethyl ether. 2 g (50% of theory) of 7-[4-(2-carbamoylethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of decomposition point 283° to 286° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][NH:36][CH:37]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38]1>>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:36]([CH3:35])[CH:37]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CNC1CCN(C)C1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Methyl-(1-methyl-pyrrolidin-3-yl)-amine following General Procedure C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.O1C2C(=CC=CC=2)CCC1.[Li]CCCC.[C:27](=[O:29])=[O:28]>C(O)(=O)C.[Zn]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:27]([OH:29])=[O:28])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Zn]
Agent: c1ccc2c(c1)CCCO2
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1OCCC2

Procedure:
The synthesis of chroman-5-carboxylic acid derivatives started with the alkylation of 3-hydroxy-benzoic acid methyl ester (36; commercially available) with propargyl bromide in the presence of K2CO3 to give phenylether (37) which was cyclised to the chromen derivative (38) by heating to reflux in N,N-diethylaniline. The carboxylic ester was saponified by treatment of (38) mith NaOH in MeOH and water and the obtained chromen derivative (39) was hydrogenated to give the desired acid (40). The corresponding chroman-8-carboxylic acid derivatives were synthesized by reduction of 4-chromanone (41; commercially available) with zinc in acetic acid and subsequent ortho-metalation of the intermediate chroman derivative (42) with n-BuLi and trapping with carbon dioxide to give the desired acid (43).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[S:25]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=2)[N:6]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3c(Cl)cccc3Cl)n2)cc1

Procedure:
The title compound was prepared from N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]acetamide (63 mg) and 2,6-dichlorobenzenesulfonyl chloride (66 mg) as described in the synthetic METHOD B to give a white solid (5.6 mg) with purity >80%: MS (pos) m/z 442.2, 444.4.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[N:10][CH:9]([NH2:12])[N:8]=2)[CH:2]=1.[C:19]([CH:22]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:23](OC)=[O:24])(=O)[CH3:20].S(O)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C(C)=CC=CC=1>[C:1]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]3[N:12]=[C:19]([CH3:20])[C:22]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:23]([OH:24])[N:10]3[N:11]=2)[CH:2]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: NC1N=NC(c2cccc(-c3ccccc3)c2)=N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1O

Procedure:
In a 100 ml RBF, equipped with a Dean-Stark trap (filled with molecular sieves), was added 5-([1,1′-biphenyl]-3-yl)-3H-1,2,4-triazol-3-amine (1.133 g, 4.80 mmol), dimethyl 2-acetylsuccinate (2.334 mL, 14.39 mmol) followed by Xylene (50 mL) and Ts-OH (9.12 mg, 0.048 mmol). The reaction was heated at reflux for 5 hrs. Filtered and washed by hexanes to collect the off-white solid, which was used directly for the next step. 1H-NMR (500 MHz, CDCl3) δ 2.26 (3H, s), 3.65 (2H, s), 3.72 (3H, s), 7.35-7.36 (1H, m), 7.44-7.46 (2H, m), 7.47-7.48 (1H, m), 7.64-7.66 (2H, m), 7.73-7.75 (1H, m), 8.13-8.15 (1H, m), 8.43 (1 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=O)[NH:9][C:8]([C:13]([NH2:15])=O)=[CH:7]2.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[CH:7]=[C:8]([C:13]#[N:15])[N:9]=1
Reactant: NC(=O)c1cc2cccc(Cl)c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2cccc(Cl)c2c(Cl)n1
Yield: 40 %

Procedure:
A solution of 8-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (0.5 g, 1.99 mmol) in POCl3 (10 mL) was heated to reflux for 4 hours. The reaction mixture was subsequently concentrated in vacuo and the crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=5:1-2:1 gradient) to give the title compound (200 mg, 40%). ESI-MS m/z [M+H]+ 223.1.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].[O-:11][C:12]#[N:13].[K+]>C(O)(=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH:4][C:12]([NH2:13])=[O:11]
Reactant: N#C[O-]
Reactant: COc1ccc(F)c(N)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(F)c(NC(N)=O)c1
Temperature: 19 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of 2-fluoro-5-methoxyaniline (35.15 g, 249 mmol) in acetic acid (99 mL) and water (177 mL) at 35° C. was added potassium cyanate (40 g, 0.49 mol) in water (170 mL) over 20 minutes under N2. The mixture was stirred at 40° C. for 20 min and at 18 to 20° C. for 2 h, and then quenched into water (500 mL). The crude product was filtered, washed with water (1.2 L), heptane (50 mL) and slurred in a mixture of tert-butylmethylether (100 mL) and ethyl acetate (5 mL) for 5 minutes at ambient temperature. The product was filtered, washed with tert-butylmethylether (30 mL) and dried in vacuo at 40° C. to give N-(2-Fluoro-5-methoxyphenyl)urea (31.75 g, 69%) as a light-brown solid.