Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=2)[CH:9]=1)[C:4](=[O:7])[CH2:5][CH3:6])[CH3:2].[NH2:21][NH:22][C:23]([NH2:25])=S>C(O)C>[CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]3[N:16]([C:23]([NH2:25])=[N:22][N:21]=3)[N:15]=2)[CH:9]=1)[C:4](=[O:7])[CH2:5][CH3:6])[CH3:2]
Reactant: CCC(=O)N(CC)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: NNC(N)=S
Solvent: CCO
Product: CCC(=O)N(CC)c1cccc(-c2ccc3nnc(N)n3n2)c1
Yield: 44.8 %

Procedure:
A solution of 5.0 g N-ethyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]propanamide and 3.2 g thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was treated and the product chromatographed as described for Example 70. Recrystalization of the product from dichloromethane-hexane afforded 2.4 g yellow crystals, mp 199°-200° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH2:1]([N:8]1[C:12]([CH:25]2[CH2:27][CH2:26]2)=[CH:11][C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)n(Cc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc(C2CC2)n(Cc2ccccc2)n1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
2.57 g of methyl 1-benzyl-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-3-carboxylate (7.06 mmol, 1.0 eq.) were dissolved in 51 mL of dry 1,2-dimethoxyethane under nitrogen atmosphere. 1.52 g of cyclopropylboronic acid (17.6 mmol, 2.5 eq.), 2.62 g of sodium carbonate (24.7 mmol, 3.5 eq.) and 408 mg of tetrakis(triphenylphosphin)palladium(0) (0.353 mmol, 0.05 eq.) were added and the mixture was stirred for 24 hours at 75° C. bath temperature. Then the mixture was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue purified by flash chromatography to give 1.61 g (5.39 mmol, 76%) of analytically pure target compound.
Reaction SMILES: [O:1]=[C:2]1[NH:17][C:6]2[N:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH:15]=O)[N:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1.Cl.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:8]2[N:9]=[CH:10][C:5]3[CH:4]=[CH:3][C:2](=[O:1])[NH:17][C:6]=3[N:7]=2)[CH2:29][CH2:28]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=CCCCOc1ncc2ccc(=O)[nH]c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1ccc2cnc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde (235 mg, 1.01 mmol) in dichloroethane (5 mL) was added 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (270 mg, 1.01 mmol) followed by Et3N (0.28 mL, 2.0 mmol, 2 equiv). After 10 min at RT, NaBH(OAc)3 (297 mg, 1.4 mmol) was added as a powder. The reaction was stirred for 2 h at room temperature and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc (with a little MeOH to help dissolve the solids). The organic layer was washed with brine and concentrated. Purification by liquid chromatography (5% MeOH/CH2Cl2 with 1% NH4OH) gave the title compound as a white solid (375 mg, 0.836 mmol, 83%). MS: APCI: M+1: 448.1 (Exact Mass: 447.12).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21](O)=[O:22])=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:21]([C:5]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)[CH2:12][CH2:11]3)=[O:9])[N:6]=2)=[O:22])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with piperazine-1-carboxylic acid tert-butyl ester, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 630.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[S:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[CH3:21][S:22]([C:25]1[CH:56]=[CH:55][C:28]([C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35](/[CH:42]=[CH:43]/[C:44]3[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][C:45]=3[S:51]([OH:54])(=[O:53])=[O:52])=[C:36]([S:38]([O-:41])(=[O:40])=[O:39])[CH:37]=2)=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH:3]([O:39][S:38]([C:36]1[CH:37]=[C:32]([NH:31][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:23])=[O:24])=[CH:56][CH:55]=2)[CH:33]=[CH:34][C:35]=1/[CH:42]=[CH:43]/[C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([S:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:5]=2)=[CH:46][C:45]=1[S:51]([O:54][CH:6]([CH3:7])[CH3:5])(=[O:52])=[O:53])(=[O:41])=[O:40])([CH3:11])[CH3:4]
Reactant: COc1ccc(C(=O)O)cc1S(=O)(=O)N1CCOCC1
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(/C=C/c3ccc(N)cc3S(=O)(=O)O)c(S(=O)(=O)[O-])c2)cc1
Product: COc1ccc(C(=O)Nc2ccc(/C=C/c3ccc(NC(=O)c4ccc(S(C)(=O)=O)cc4)cc3S(=O)(=O)OC(C)C)c(S(=O)(=O)OC(C)C)c2)cc1S(=O)(=O)N1CCOCC1

Procedure:
From 4-methoxy-3-(morpholine-4-sulfonyl)-benzoic acid, Example 1a and 5-[[4-(methylsulfonyl)benzoyl]amino]-2-[(E)-2-[4-amino-2-sulfophenyl]ethenyl]benzenesulfonate, bis(1-methylethyl) ester, Example 28b (52%): MS (−ESI): [M−H]− 918.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[O:19][C:18]([C@@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[N:17][N:16]=2)=[N:4][C:5]([O:13][CH3:14])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:7]=1Cl.[CH3:27][C:28]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:15]2[O:19][C:18]([C@@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[N:17][N:16]=2)=[N:4][C:5]([O:13][CH3:14])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:7]=1[CH:27]=[CH2:28]
Reactant: COc1nc(-c2nnc([C@](C)(O)C(F)(F)F)o2)c(N)c(Cl)c1C(F)(F)F
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=Cc1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-(5-(3-amino-4-chloro-6-methoxy-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Ex 13.1) (160 mg, 0.393 mmol) in MeCN (1 ml) was added bis(triphenyl phosphine)palladium(II) chloride (Aldrich) (83 mg, 0.118 mmol) followed by 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Sigma Aldrich)(0.087 ml, 0.511 mmol). 2M Sodium carbonate (0.885 ml, 1.770 mmol) was added and the resulting mixture was heated at 130° C. for 30 minutes using microwave radiation. The mixture was filtered through Celite® and washed through with EtOAc. The filtrate was diluted further with EtOAc (50 ml) and washed with sat.NaHCO3, water, brine and dried over MgSO4. Isolute Si-TMT (2,4,6-trimercaptotriazine silica, palladium scavenger) was added the mixture was stirred for 30 mins and filtered. The solvent was removed in vacuo to afford the title compound which was used without further purification;
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)=[O:5])[CH3:2].[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10](=[O:12])[NH:22][C:18]2[CH:17]=[C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=[CH:20][CH:19]=2)[CH:8]=1)[CH3:2]
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)Cc1cccc(C(=O)O)c1
Product: CCOC(=O)Cc1cccc(C(=O)Nc2cccc(-c3ccccc3)c2)c1

Procedure:
3-Ethoxycarbonylmethyl-benzoic acid (126 mg, 0.61 mmol) was coupled to biphenyl-3-ylamine (105 mg, 0.62 mmol) using Method C. The residue was purified by column chromatography eluting with 100% DCM to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][S-:13].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:13][CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Product: CSc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A mixture of 3,4-difluoro-nitrobenzene (25 g, 0.157 mol) and sodium methanethiolate (10.5 g, 0.15 mol) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted twice with ether. The extracts were combined, washed with water (twice) and brine, dried (sodium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 17% dichloromethane/hexanes to give 2-fluoro-1-methylsulfanyl-4-nitro-benzene (18.6 g, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:17]=1.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][OH:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)oc1cc(Br)ccc12
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)oc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
A cloudy solution of 3-bromo-dibenzofuran-7-carboxylic acid (3.2 g, 10.9 mmol) in 80 ml THF was cooled to 0° C. and a solution of borane in THF (1.0M, 13.0 ml, 13.0 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred at room temperature for 20 hours and was then quenched by the cautious addition of methanol (10 ml). The solution was evaporated to dryness in vacuo and the residue was dissolved in methanol-CH2Cl2 (1:1) and again evaporated. After one repetition of this dissolution-evaporation process, 2.74 g (90%) of the title compound was obtained as a brown solid and used in the next reaction without purification.
Reaction SMILES: [BH4-].[Na+].Cl.[I:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]=2)=[CH:7][CH:6]=1>CO>[I:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][NH:12]2)=[CH:9][CH:10]=1
Reactant: COc1ccc2c(c1)CCN=C2c1ccc(I)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCNC2c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Sodium borohydride (2 g, 52.9 mmol) was added in small portions to a solution of 1-(4-iodophenyl)-6-methoxy-3,4-dihydroisoquinoline hydrochloride (7.5 g, 18.7 mmol) in MeOH (100 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, then quenched by the dropwise addition of H2O (20 ml). The resulting mixture was concentrated in vacuo to remove most of the MeOH, then EtOAc was added. The resulting mixture was extracted with 1M NaOH (2×25 ml), then saturated NaCl solution (25 ml), dried over MgSO4, and evaporated in vacuo to give 6.2 g (65% yield) of white solid.
Reaction SMILES: [C:1]([CH:4]([CH2:12][C:13]1[C:17]2[CH:18]=[C:19]([N:22]3[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]3=[O:34])[CH:20]=[CH:21][C:16]=2[S:15][N:14]=1)C(OC(C)(C)C)=O)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:33][N:24]1[C:25]([C:29]([F:30])([F:31])[F:32])=[CH:26][C:27](=[O:28])[N:22]([C:19]2[CH:20]=[CH:21][C:16]3[S:15][N:14]=[C:13]([CH2:12][CH2:4][C:1](=[O:3])[CH3:2])[C:17]=3[CH:18]=2)[C:23]1=[O:34]
Reactant: CC(=O)C(Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of tert-butyl α-acetyl-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-propionate (0.700 g) and trifluoroacetic acid (10.0 mL) in methylene chloride is stirred overnight at room temperature, concentrated in vacuo, and diluted with methylene chloride and saturated sodium hydrogen carbonate solution. The phases are separated. The organic phase is dried over anhydrous magnesium sulfate and concentrated in vacuo to give 1-methyl-3-[3-(3-oxobutyl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione as a white solid (0.310 g, mp 198-199° C.). The aqueous phase is acidified with concentrated hydrochloric acid, stirred for several minutes, and filtered to obtain a solid. The solid is washed with water and air-dried to give α-acetyl-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-propionic acid as a white solid, mp 191-193° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 37.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (195 mg, yield: 37.8%).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].S(O)(O)(=O)=O.[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[NH2:29].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]2[N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][C:14]([CH3:15])=[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: Nc1ncc[nH]1
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nccn2C1c1ccc(C#N)cc1
Temperature: 65 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
Under an atmosphere of argon, ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (1.42 g, 5.82 mmol) and 1H-imidazole-2-amine sulfate (2:1) (1000 mg, 3.78 mmol, 0.65 eq.) were dissolved in DMF (10 ml), and solid sodium bicarbonate (1.96 g, 23.3 mmol, 4 eq.) was added. The mixture was stirred at 65° C. for 12 h. The mixture was then filtered through kieselguhr, and the DMF from the filtrate was distilled off under reduced pressure. Acetonitrile (10 ml) was added to the residue. The precipitated product was filtered off, washed with ethanol and dried under high vacuum, which gave a first product fraction (503 mg). The concentrated filtrate was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA) and lyophilized. This gave 778 mg as a further product fraction (total yield: 71% of theory).
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[N:12][C:13]=1[Cl:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][CH:2]([F:6])[C:3]([F:5])([F:4])[O:15][C:10]1[CH:11]=[N:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=1
Reactant: Oc1cnc(Cl)c(Cl)c1
Reactant: FC(F)=C(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(Cl)C(F)(F)Oc1cnc(Cl)c(Cl)c1

Procedure:
Chlorotrifluoroethylene was passed into a mixture of 16.4 g (0.1 mol) of 5,6-dichloro-3-pyridinol I/29 and 20 g (0.145 mol) of anhydrous potassium carbonate in 100 ml of absolute acetonitrile at 35° C. until starting material was no longer present. The solid was filtered off under suction, the solvent was removed by distillation, and the residue was taken up in ether and washed until neutral. After drying over MgSO4 and removal of the ether by distillation, the residue was distilled in a high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:36](=[O:37])[CH2:35][C:30]1[NH:29][C:28]2[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=2[S:32](=[O:33])(=[O:34])[N:31]=1)=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@H]1CCCC[C@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude (1S,2R)-2-(4-fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester (4.97 mmol) was dissolved in N,N-dimethylformamide (40 mL) at 25° C. and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 1.47 g, 4.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.887, 4.63 mmol), and N-methylmorpholine (1.01 mL, 9.19 mmol) were added sequentially. The reaction mixture was stirred at 25° C. for 2 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, decanted, and were concentrated in vacuo to afford the crude product, (1S,2R)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid methyl ester as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][C:15]([NH:19]CC4C=CC(OC)=CC=4OC)=[N:14][C:13]=3[N:12]([C:31]([CH3:42])([CH3:41])[CH2:32][O:33][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:43][C:44]1[N:48]([CH2:49][C:50](O)=[O:51])[N:47]=[C:46]([C:53]([F:56])([F:55])[F:54])[CH:45]=1>>[NH2:19][C:15]1[N:16]=[CH:17][C:18]2[C:10]([C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:50](=[O:51])[CH2:49][N:48]4[C:44]([CH3:43])=[CH:45][C:46]([C:53]([F:56])([F:55])[F:54])=[N:47]4)[CH:7]=[N:6][CH:5]=3)=[O:9])=[CH:11][N:12]([C:31]([CH3:41])([CH3:42])[CH2:32][OH:33])[C:13]=2[N:14]=1
Reactant: COc1ccc(CNc2ncc3c(C(=O)c4cncc(N)c4)cn(C(C)(C)CO[Si](C)(C)C(C)(C)C)c3n2)c(OC)c1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)Nc1cncc(C(=O)c2cn(C(C)(C)CO)c3nc(N)ncc23)c1

Procedure:
The title compound was prepared according to the method described for Example 46 using (5-aminopyridin-3-yl){7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-[(2,4-dimethoxybenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (see Preparation 51) and (5-methyl-3-trifluoromethyl-pyrazol-1-yl)acetic acid (46.8 mg, 0.225 mmol) to afford the title compound as a brown solid in 79% yield, 82 mg.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12]CC)=O)[CH:4]=[CH:5][N:6]=1.[C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH3:19].[Li]>>[C:22]([O:21][C:18](=[O:20])[CH2:19][C:10]([C:9]1[CH:15]=[CH:16][CH:17]=[C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:8]=1)=[O:12])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cccc(-n2ccnc2C)c1
Agent: [Li]
Product: Cc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
Prepared from ethyl 3-(2-methyl-imidazol-1-yl)-benzoate [prepared by reaction of ethyl 3-aminobenzoate with ethyl acetimidate hydrochloride in EtOH at 0° C., direct treatment with aminoacetaldehyde diethyl acetal in EtOH at 23° C., follwed by addition of conc. H2SO4 and refluxing.] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a brown oil (9.66 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC.C(OCC)(=O)C.[F-].[K+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:9]=[CH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cc(I)ccn1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1ccnc(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
A mixture of 2-fluoro-4-iodopyridine (2.23 g, 10.0 mmol), tributyl vinyl tin (3.8 g, 12 mmol), and Pd2Cl2(PPh3)2 (703 mg, 1.0 mmol) in dioxane (20 mL) was heated under nitrogen at 80° C. overnight. After cooled, ethyl acetate (40 ml) and saturated KF aqueous solution were added to the reaction mixture. The mixture was stirred for 30 min. The organic layer was separated and washed with water, dried (MgSO4), and concentrated. The resulting residue was purified by flash column chromatography eluting with hexane/ethyl acetate (20:1) to provide the title compound (463 mg, 38%). 1HNMR (500 MHz, CDCl3) δ ppm 5.55 (d, J=10.92 Hz, 1 H) 5.99 (d, J=17.47 Hz, 1 H) 6.67 (dd, J=17.47, 10.61 Hz, 1 H) 6.88 (m, 1 H) 7.17 (dt, J=5.30, 1.56 Hz, 1 H) 8.16 (d, J=5.30 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:28](Cl)(=[O:30])[CH3:29]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([NH:24][C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18]2)[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cc(F)cc2n1
Product: CC(=O)Nc1cccc(CCN2CCN(c3cc(F)cc4nc(C)ccc34)CC2)c1
Yield: 46 %

Procedure:
The title compound was prepared in 46% yield according to the general procedure for the preparation of amides (Method B) starting from 3-{2-[4-(7-fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline and acetyl chloride: