Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32]>>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[C:19]=1[CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:6]2[C:5]3[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=3)[N:8]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[CH:7]=2)=[O:12])[CH2:14][CH2:15]1
Reactant: CN1CCN(C(=O)CCl)CC1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3ccccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1.[OH-].[NH4+].[CH:22](O)=[O:23]>>[CH2:18]([O:17][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][CH:22]=[O:23])[N:8]=2)=[CH:10][CH:11]=1)=[O:16])[CH3:19]
Reactant: O=CO
Reactant: CCOC(=O)c1ccc(-c2cccc(CN)n2)cc1
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(-c2cccc(CNC=O)n2)cc1

Procedure:
A solution of 6-aminomethyl-2-(p-ethoxycarbonylphenyl)pyridine (10.76 g) in 10 ml of formic acid is heated at 90° for 15 hours. The reaction is cooled to 0°, basified with excess saturated ammonium hydroxide solution and extracted with chloroform (4×30 ml). The organic extracts are dried and evaporated to yield 2-(p-ethoxycarbonylphenyl)-6-formylaminomethylpyridine which is recrystallized from toluene, m.p. 119.5°-120.5°.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2[nH]c3ccccc3c2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCc2c(c3ccccc3n2S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3 g of 1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester in methylene chloride (50 mL) is treated with 0.982 g of sodium hydroxide and stirred and room temperature overnight. Benzenesulfonylchloride (6.30 mL) is added to the reaction and stirred at room temperature overnight. The reaction mixture is diluted with water (250 mL) and extracted with methylene chloride. The organics are combined, washed with water then a saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 5-benzenesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester as a yellow powder. MS (m/z): 385 (M+1).
Reaction SMILES: O.[CH:2]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](C=O)[C:4]=2[CH:3]=1.S(=O)(O)[O-:13].[Na+]>C(#N)C>[OH:13][C:5]12[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]1[CH2:3][CH2:2]2
Reactant: O=S([O-])O
Reactant: O=Cc1cccc2c1C=C2
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: OC12C=CC=CC1CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of the thus prepared permonophosphoric acid (18 mL, 1.2M) in acetonitrile was added to a flask equipped with ice bath, stirrer and water-cooled condenser. To the stirred solution was added 3-benzocyclobutene aldehyde (5 g, 0.037 moles) dropwise over a period of 30 minutes. The reaction mixture was stirred for an additional 2 hours and cooled to 0° C. Water (20 mL) was added to the cooled reaction mixture, followed by the addition of sodium bisulfite solution until the reaction mixture was free from permonophosphoric acid, as tested with starch iodide paper. The organic solvent was removed by rotary evaporation, and sodium hydroxide was added until the reaction mixture became alkaline. The reaction mixture was cooled to 0° C., acidified and extracted with ethyl acetate. The organic layer was washed with water, sodium bicarbonate and brine. Drying and removal of the solvent was followed by flash chromatography using 10 percent ethyl acetate in hexanes to afford 3.19 g 3-hydroxybenzocyclobutene as a solid. This represents a yield of approximately 70 percent. The 3-benzocyclobutene phenol was recrystallized from pentane. The 3-benzocyclobutene phenol product has a melting point of 47° C. Product analysis indicated substantially complete conversion of 3-benzocyclobutene aldehyde with the product, other than the desired 3-hydroxybenzocyclobutene, comprising unidentified polymer-like substance with substantially no formation of 3-benzocyclobutene carboxylic acid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:35])[C:18]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)([CH3:20])[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:38]I>CN(C)C=O>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]([CH3:38])[C:17](=[O:35])[C:18]([C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)([CH3:20])[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a solution of 154 mg (0.3 mmol) of N-(2-benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramide in 1 ml dimethylformamide were added 26 mg (0.6 mmol) sodium hydride (55% suspension in mineral oil). After 30 min stirring at room temperature 85 mg of methyl iodide (0.6 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography to yield 51 mg (32%) of the title compound as white crystals. M.p. 89-91° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]2[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]2)=[N:4][C:5](S(CC)(=O)=O)=[N:6][C:7]=1[C:8]#[N:9].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:15]2[CH2:16][CH2:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20]2)=[N:4][C:5]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:6][C:7]=1[C:8]#[N:9]
Reactant: CCS(=O)(=O)c1nc(C#N)c(Cl)c(N2CCS(=O)(=O)CC2)n1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: N#Cc1nc(N2CCNCC2)nc(N2CCS(=O)(=O)CC2)c1Cl

Procedure:
1.8 gm (0.005 mol) of 5-chloro-6-cyano-4-(1,1-dioxido-thiomorpholino)-2-ethylsulfonyl-pyrimidine (m.p. 234°-237°C, obtained from 2-ethylthio-5-chloro-6-cyano-4-thiomorpholino-pyrimidine by oxidation with potassium permanganate in dilute hydrochloric acid) were slowly added to a solution of 2.6 gm (0.03 mol) of piperazine in 50 ml of dioxane. After standing for a short time, the reaction solution was evaporated almost to dryness in vacuo, and the residue was taken up in about 50 ml of water. The insoluble reaction product was suction-filtered off, washed with water and dried. Yield: 1.4 gm (78% of theory).
Reaction SMILES: Br[C:2]1[C:3]([O:21][C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]=2)=[N:6][CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)(O)[O-].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[O:21][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]=2)[N:6]=[CH:7][C:2]=1[C:32]1[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)CCc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CCc1csc(Nc2cc(Oc3c(F)cccc3F)c(-c3cccnc3)cn2)n1
Temperature: 80 °C

Procedure:
Ethyl 3-(2-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)propanoate (0.1932 mmol), pyridin-3-ylboronic acid (0.02850 g, 0.2319 mmol), Pd(PPh3)4 (0.02233 g, 0.01932 mmol), in DME (10 mL), and 2M sodium bicarbonate (2 mL) are combined and heated to 80° C. overnight. The reaction mixture is cooled and partitioned between CH2Cl2 and water. The combined organic layers are dried, filtered, and concentrated. The residue is purified by silica gel, eluting with 30-40% EtOAc in hexane, to afford ethyl 3-(2-(4-(2,6-difluorophenoxy)-3,3′-bipyridin-6-ylamino)thiazol-4-yl)propanoate.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=O)C.O=S(Cl)Cl.[CH3:22][N:23]1[C:27]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][C:36]=3[NH2:38])[CH:31]=[CH:30]2)=[CH:26][N:25]=[CH:24]1>C1COCC1>[OH:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]/[C:15]([NH:38][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:37]=2[N:29]([CH2:28][C:27]2[N:23]([CH3:22])[CH:24]=[N:25][CH:26]=2)[CH:30]=[CH:31]3)=[O:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC(C)=O
Reactant: Cn1cncc1Cn1ccc2cccc(N)c21
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)Nc2cccc3ccn(Cc4cncn4C)c23)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
(E)-3-(3-Acetoxy-4-methoxyphenyl)acrylic acid (0.099 g, 0.420 mmol) was suspended in dry THF (8 ml). SOCl2 (0.037 ml, 0.504 mmol) was added and the mixture was stirred at RT for 1 h. The solvent was evaporated to dryness and the residue was dissolved in dry THF (8.00 ml). TEA (0.059 ml, 0.420 mmol) and 1-(3-methyl-3H-imidazol-4-ylmethyl)-1H-indol-7-ylamine (0.095 g, 0.420 mmol) were added. The mixture was stirred at RT for 18 hrs, heated at reflux for hrs and then at RT for 48 hrs. The solvent was removed in vacuo and the residue was partitioned between EtOAc (10 ml) and H2O (2×10 ml). Organic phase was dried over sodium sulphate and concentrated to dryness. The crude was charged onto a SCX cartridge and eluted firstly with MeOH and then with NH3/MeOH. The title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-[1-(3-methyl-3H-imidazol-4-ylmethyl)-1H-indol-7-yl]-acrylamide (56 mg) was obtained after column chromatography (eluent: DCM 100% to DCM/MeOH 98:2).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]#[N:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]21[CH2:20][CH2:19][CH2:18][CH2:17]2.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]3[NH:23][N:22]=[N:21][N:16]=3)=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]21[CH2:20][CH2:19][CH2:18][CH2:17]2
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1cc2c(c(Cl)c1Cl)C(=O)C1(CCCC1)C2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2c(cc(OCc3nnn[nH]3)c(Cl)c2Cl)CC12CCCC2

Procedure:
The title compound is prepared following substantially the same procedure described in Example 38, Step B, using the following substances: [1'-oxo-6',7'-dichlorospiro(cyclopentane-1,2'-indan)-5'-yloxy]acetonitrile (5.3 g.), sodium azide (1.44 g.), ammonium chloride (1.14 g.) and dimethylformamide (35 ml.). This procedure affords 5.0 g. (83%) of 5-[1'-oxo-6',7'-dichlorospiro(cyclopentane-1,2'-indan)5'-yloxymethyl]tetrazole which after recrystallization from acetonitrile melts at 191° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][N:73]3[C:84](=[O:91])[C@@H:85]([NH2:90])[C:86]([CH3:89])([CH3:88])[CH3:87])=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:90][C@H:85]([C:84]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:54][CH2:55][CH2:56][CH2:57]3)(=[O:60])=[O:59])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:82])([CH3:81])[C:76]32[CH2:79][CH2:78][CH2:77]3)[CH2:74]1)=[O:91])[C:86]([CH3:89])([CH3:88])[CH3:87])[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](N)C(C)(C)C)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCCCC1)C(C)(C)C)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 15 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(1-methyl-cyclohexyl)-acetic acid (0.217 g; 0.80 mmol) (prepared according to Tetrahedron Let. 2007, 48, 6343-6347) and HATU (0.38 g; 1.00 mmol) in DCM (10 mL) was stirred for 20 min at ambient temperature. After addition of DIPEA (0.698 mL; 4.00 mmol) and (5R,8S)-7-((S)-2-Amino-3,3-dimethyl-butyryl)-10,10-dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.400 g; 0.67 mmol) in DCM (10 mL) the reaction mixture was stirred for 15 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.91 min; M/z=818 [M+H], HPLC (method A3) Rt=7.18 min
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:18])C(=O)C1>C(#N)C>[Br:18][C:6]1[C:7]([NH2:10])=[N:8][CH:9]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc(C2CC2)cn1
Solvent: CC#N
Product: Nc1ncc(C2CC2)nc1Br

Procedure:
A solution of 5-cyclopropylpyrazin-2-amine (79 mg, 0.584 mmol) in acetonitrile (10 mL) was cooled down to 0° C., and treated with gradual addition of NBS (140 mg, 1.46 mmol) over the course of 1 hour while closely monitoring reaction progress by LCMS. The reaction mixture was concentrated and the residue was triturated with EtOAc (2×5 mL) and the EtOAc supernatants were separated via centrifugation, combined and washed with 1N NaOH (3×1 mL) and the EtOAc layer was dried (over Na2SO4), concentrated and a crude brown reside was obtained. The crude product was further purified by flash chromatography on silica gel eluted with gradient EtOAc/CH2Cl2 (0-30%) to afford 3-bromo-5-cyclopropylpyrazin-2-amine in colorless solid (38.2 mg, 38.5% yield). LCMS (m/z): 214.0/216.0 (MH+), 0.64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:28]=[CH:27][C:26]([S:29](=[O:35])(=[O:34])[NH:30][CH:31]2[CH2:33][CH2:32]2)=[CH:25][C:19]=1[C:20]([N:22]=[C:23]=[O:24])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:28]=[CH:27][C:26]([S:29]([NH:30][CH:31]2[CH2:33][CH2:32]2)(=[O:35])=[O:34])=[CH:25][C:19]=1[C:20]1[NH:22][C:23](=[O:24])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C=NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2cc(S(=O)(=O)NC3CC3)ccc2Cl)nn1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.050 g, 0.20 mmol), 2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl isocyanate (step-4 of Intermediate-40, 0.123 g, 0.41 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.025 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 0.39-0.41 (m, 2H), 0.49-0.52 (m, 2H), 2.17-2.20 (m, 1H), 7.52-7.55 (d, J=8.0 Hz, 2H), 7.91-8.00 (m, 5H), 8.14 (m, 1H), 12.60 (br s, 1H); MS (m/z): 425.10 (M+).
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)O1.[H-].[Na+].[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>>[N:10]1([C:6]2[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:6]3[C:5]4[C:26](=[CH:25][CH:29]=[CH:16][CH:4]=4)[CH2:27][C:2]=3[C:7]=2[C:8]#[N:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCOC1
Reactant: Cc1ccc(-c2cc(N3CCCCC3)c(C#N)c(=O)o2)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3)cc1

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-6-p-tolyl-2H-pyran-3-carbonitrile (294 mg), indanone-2, (132 mg) and NaH (29 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 162-164° C.; ESMS 365 (M++1); IR (KBr) 2213 cm−1 (CN); HRMS calcd. for C26H24N2 364.1940 found 364.1936.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([OH:25])=[O:24])[CH:13]=1.O[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1.C(Cl)Cl>[N:32]1([CH2:31][CH2:30][O:24][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:14]3[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=3)[CH:21]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: OCCN1CCOCC1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)O)c2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)OCCN3CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 43.9 %

Procedure:
4-Dimethylaminopyridine (4.4 mg, 0.036 mmol) is added to a stirred solution of 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid (100 mg, 0.24 mmol), N-(2-hydroxyethyl) morpholine (29.07 μL, 0.24 mmol) and 1,3-dicyclohexylcarbodiimide (0.31 mL, 1 M solution in DCM) in dry THF/DCM (6 mL, 1:1) and the reaction mixture is stirred for 5.5 hours at room temperature under nitrogen atmosphere. The mixture is filtered over a pad of Celite and the filtrate concentrated under reduced pressure. The residue is dissolved EtOAc (30 mL), washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by chromatography (SiO2 packed column) eluting with ethyl acetate/heptane to afford 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid 2-morpholin-4-yl-ethyl ester (56 mg, Example 75). LCMS: RT=2.07 minutes, MS: 534 (M+H); 1H NMR, (300 MHz, CDCl3): □8.62 (1H, s), 8.3 (1H, d, J=3.5 Hz), 8.1 (1H, d, J=3.5 Hz), 7.55 (1H, t, J=3.5 Hz), 7.42 (1H, s), 7.2 (2H, s), 6.48 (1H, s), 5.04 (1H, b), 4.5 (2H, t, J=2 Hz), 4.05 (3H, s), 3.72 (6H, t, J=2 Hz), 3.1 (2H, t, J=2 Hz), 2.8 (2H, t, 2 Hz), 2.6 (4H, t, 2 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N:17]1[C:21]([CH3:22])=[N:20][C:19]([NH2:23])=[N:18]1.[O-]C1C=CC=CC=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.O>[CH3:16][N:17]1[C:21]([CH3:22])=[N:20][C:19]([NH:23][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:18]1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Cc1nc(N)nn1C
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cn(-c2ccc(Nc3nc(C)n(C)n3)cc2C#N)cn1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile (50 mg, 0.19 mmol), 1,5-dimethyl-1H-1,2,4-triazol-3-amine (45 mg, 0.40 mmol), sodium phenoxide (66 mg, 0.57 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (3 mg, 0.003 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene=Xanthphos (7 mg, 0.012 mmol) in 5 ml of dioxane was heated to 80° C. under argon for 2 hours. The mixture was diluted with water, extracted with ethyl acetate and the product purified by chromatography on silica gel using dichloromethane/methanol 9:1 v/v as an eluent. The title compound was obtained as a yellowish solid (6 mg, 11%). MS ISN (m/e): 292.3 (100) [(M−H)−].
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([O:6][C:7]2[CH:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=2)=[C:4]([I:17])[CH:3]=1.[CH2:18]([OH:21])[CH2:19][OH:20].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:20][CH2:19][CH2:18][OH:21])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:17])[CH:3]=1
Reactant: OCCO
Reactant: Clc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 33.3 %

Procedure:
A mixture of 2-(4,5-dichloro-2-iodophenoxy)-4-chloropyridine (0.45 g, 1.128 mmol), ethane-1,2-diol (4 mL, 71.89 mmol), K2CO3 (0.45 mg, 3.26 mmol) in acetone (6 mL) was stirred at 120° C. for 5 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed withed brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1 to 4:1) to afford the desired product (160 mg, 33% yield). ESI-MS m/z: 426.0[M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([OH:17])=[O:16].[N:18]12CCCN=C1C[CH2:22][CH2:21][CH2:20][CH2:19]2.BrCCCC#N.CN(C)C=O>O>[C:19]([CH2:20][CH2:21][CH2:22][O:16][C:15]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[OH:1])=[O:17])#[N:18]
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)ccc1O
Reactant: C1CCC2=NCCCN2CC1
Agent: N#CCCCBr
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCOC(=O)c1cc(-c2ccc(O)cc2)ccc1O
Temperature: 75 °C
Yield: 70.6 %

Procedure:
A mixture of 4,4′-dihydroxy-3-biphenylcarboxylic acid (2.3 g; 10 mmol), 1,8-diaza-bicyclo[5.4.0]undec-7-ene (1.7 g; 11.2 mmol), 4-bromobutyronitrile (1.7 g; 11.2 mmol) and N,N-dimethylformamide (40 ml) was heated at 75° C. for 4 h. The reaction mixture was cooled, poured into water (300 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and with water (2×100 ml), dried over magnesium sulphate and filtered. The organic solvent was removed in vacuo. The residue (3.0 g) was purified by flash chromatography using a silica gel column and toluene/ethyl acetate (97:3) as eluent to give 2.1 g (70%) of 3-cyanopropyl-4,4′-dihydroxy-3-biphenylcarboxylate.