Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[C:22]4[C:17](=[CH:18][C:19]([CH:23]=[C:24]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[NH:26][C:25]5=[O:33])=[CH:20][CH:21]=4)[NH:16][N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:34][O:35]C1C=C2C(=CC=1)NC(=O)C2>>[CH3:34][O:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:33])[C:24]2=[CH:23][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:9][CH:10]=3)=[N:15][NH:16]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: CN1CCN(c2ccc(-c3n[nH]c4cc(C=C5C(=O)Nc6ccccc65)ccc34)cn2)CC1
Product: COc1ccc2c(c1)C(=Cc1ccc3c(-c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2

Procedure:
According to the procedure for the synthesis of 3-((3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazol-6-yl)methylene)indolin-2-one, except substituting 5-methoxyoxindole (28 mg, 0.087 mol), the title compound was prepared as a yellow solid (14.4 mg, 35%). A mixture of (E)- and (Z)-isomers (83:17 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) 8.74 (d, J=2.3 Hz, 1H), 8.14 (dd, J=8.8, 2.3 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.87 (d, J=10.0 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 7.01 (d, J=8.8, 1H), 6.83 (s, 2H), 3.75-3.69 (br. m, 4H), 3.62 (s, 3H), 2.82-2.76 (br. m, 4H), 2.51 (s, 3H); MS ESI 467.2 [M+H]+, calcd for [C27H26N6O2+H]+ 467.21.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.CN(C)[CH:26]=[O:27]>>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(c2ccccc2)Oc2cc(F)ccc21
Product: O=CC1=C(Cl)c2ccc(F)cc2OC1c1ccccc1
Reaction time: 1 h

Procedure:
As in example 1, but using 10 g 7-fluoro-flavanone, 100 ml dimethylformamide and 15 ml phosphorous oxychloride. Reaction time is one hour and a half at 50° C. After hydrolysis and usual work up, the residual solid is recrystallised in hexane. Pure yellow crystalline 4-chloro-7-fluoro-3-formyl-flav-3-ene is obtained; m.p. 110°-112° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[NH:26]1[CH2:29][CH2:28][C:27]1=[O:30]>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:26]4[CH2:29][CH2:28][C:27]4=[O:30])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CCN1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCC4=O)cc3F)CC2)c(C)c1
Yield: 54.7 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (410 mg) described in Preparation Example 111 and 2-azetidinone (75 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (219 mg) was obtained.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH2:8][CH2:7][CH2:6][C:5]([CH3:10])([CH3:9])[C:4]=1[CH:11]=[CH:12][CH:13]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14].[H-].[Na+].[CH3:36][C:37]1[C:44]([CH3:45])=[C:43]([O:46][CH3:47])[CH:42]=[C:41]([CH3:48])[C:38]=1[CH:39]=O.O>CN(C)C=O>[CH3:47][O:46][C:43]1[CH:42]=[C:41]([CH3:48])[C:38]([CH:39]=[C:13]([CH3:14])[CH:12]=[CH:11][C:4]2[C:5]([CH3:9])([CH3:10])[CH2:6][CH2:7][CH2:8][C:3]=2[CH3:2])=[C:37]([CH3:36])[C:44]=1[CH3:45]
Reactant: COc1cc(C)c(C=O)c(C)c1C
Reactant: CC1=C(C=CC(C)[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(C=C(C)C=CC2=C(C)CCCC2(C)C)c(C)c1C

Procedure:
A solution of [4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-yl]triphenylphosphonium bromide (prepared from 17.2 g of 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-ol and 30.4 g of triphenylphosphonium hydrogen bromide in 150 mL of N,N-dimethylformamide (DMF)) was stirred under nitrogen in an ice bath and NaH (4.25 g, 50% oil dispersion) was added in portions. The mixture was stirred in the cooling bath for an additional hour and a solution of 2,3,6-trimethyl-p-anisaldehyde (15.8 g, 0.089 mol) in 50 mL of DMF was added dropwise within 15 min. The resulting mixture was stirred at room temperature for 18 hrs and heated to 50°-60° C. for 11/2 hrs. After cooling, the mixture was poored into 3 liters of water and extracted with hexane. The hexane extract was washed with 400 mL of a MeOH:H2O mixture (6:4, v/v) and water (400 mL). After drying over Na2SO4, the solvent was evaporated in vacuo to give 24.1 g of crude product as a brown oil. The pure product was obtained as a pale yellow oil from vacuum distillation of the crude product, bp. 152°-153° C. (0.075 mm of Hg); MS (CI): 339 (m+ +1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:30])[C:5]=2[NH:4][N:3]=1.O1CCCC1.CO.O.O.[OH-].[Li+]>>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:30])[C:5]=2[NH:4][N:3]=1
Reactant: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 50 %

Procedure:
(S)-Methyl 2-(1,4-dichloro-8-oxo-9-(2-(piperidin-1-yl)ethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (260 mg, 0.573 mmol) was dissolved in a mixture of tetrahydrofuran (5.0 mL, 61.6 mmol) and methanol (5.0 mL, 123 mmol). Water (5.0 mL, 278 mmol) was added to the mixture followed by lithium hydroxide hydrate (65 mg, 1.549 mmol). Mixture was warmed to 50° C. and held with stirring for 4.5 hours. Mixture was cooled to room temperature. Organic solvents were removed from the mixture by roto-vap. Residue was neutralized with 1.6 mL 1N hydrochloric acid and treated with ethyl acetate. Mixture sat at room temperature for 20 minutes allowing solids to form. Solids were filtered off and washed with water. Solids were dried in vacuo. Title compound was obtained as white solid in 50% yield. MS (M−H)−=437.1, 439.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[C:22]([C:24]([NH2:26])=[O:25])[CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[C:29](O)([C:31](F)(F)F)=O.C([SiH](CC)CC)C.C(=O)C>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[C:22]([C:24]([NH:26][CH2:29][CH3:31])=[O:25])[CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(N)=O)ccc1OCC2)c1ccccc1Cl
Agent: CC=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCNC(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccccc3Cl)cc1CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N2-(2-chlorophenyl)-N2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,9-dicarboxamide 119 (70 mg), TFA (37.5 μL), triethylsilane (80 μL) and acetaldehyde (28 μL) in dry MeCN (Dube et al (1999) Tat. Letters 40(12):2295-2298) was stirred at room temperature overnight then concentrated in vacuo. Purification on silica yielded 300. NMR: (CDCl3 δ 7.19 ppm): 1.21 (t, 3H, CH3, J=7.28 Hz), 2.93 (t, 2H, CH2, J=5.07 Hz), 3.32 (s, 3H, CH3), 3.43 (m, 2H, CH2), 4.17 (t, 2H, CH2, J=5.10 Hz), 5.94 (m, H, NH), 6.59 (s, H, ArH), 6.91 (d, H, ArH, J=8.41 Hz), 7.29-7.36 (m, 3H, 3×ArH), 7.44-7.47 (m, 2H, 2×ArH), 7.81 (m, H, ArH). MS: (ESI+) MH+ 482.15
Reaction SMILES: [I:1]Cl.ClCCl.[Cl:6][C:7]1[N:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1>CN1CCCC1=O.N1C=CC=CC=1>[Cl:6][C:7]1[N:8]=[C:9]2[C:15]([I:1])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1
Reactant: Clc1cnc2[nH]ccc2n1
Reactant: ClI
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Clc1cnc2[nH]cc(I)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A 1M solution of iodine chloride in dichloromethane (4 ml, 4 mmol) was added dropwise to an ice-cold solution of 2-chloro-5H-pyrrolo[2,3-b]pyrazine (4) in N-methylpyrrolidone (residual from previous step) and pyridine (5 ml). The reaction mixture was stirred for 60 minutes at 0° C. and then was concentrated in vacuo. The residue was purified by flash chromatography, using as eluent pentane/EtOAc 0% to 50%, to give the title compound (820 mg, 75% over two steps). 1H NMR (DMSO-d6) 8.2 (1H, s), 8.4 (1H, s). MS (ES+): 280
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=[O:14].[H-].[Na+].BrC[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[N+:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH2:1][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3](=[O:14])[NH:4]2)([O-:13])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(CC(=O)OCC)C(=O)Nc2cccc([N+](=O)[O-])c21
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitro-1,3-dihydro-2H-indol-2-one (5.25 g, 29.5 mmol, described in Intermediate 17) in DMF (200 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil; 1.24 g, 30.9 mmol) and the resulting mixture was stirred for 30 min. Ethyl bromoacetate (3.60 mL, 32.4 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 h. A further equivalent of sodium hydride (60% dispersion in mineral oil; 1.24 g, 30.9 mmol) was added, stirring was continued for 1 h, then ethyl bromoacetate (3.00 mL, 27.1 mmol) was added dropwise. The reaction mixture was stirred for 1 h, then quenched with saturated aqueous NH4Cl (125 mL) and H2O (500 mL). The mixture was extracted with EtOAc (3×300 mL) and the combined organic extracts were washed with brine (100 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=351 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([NH:15][N:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>C1(C)C=CC=CC=1.CN(C)N>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([N:15]([CH3:25])[N:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: CN(C)N
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Temperature: 5 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
To a 50 mL volume three-necked flask, 1.0 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(phenylmethylidene)hydrazine ((40-a)-(14)-6), 3.5 ml of toluene and 629 mg of potassium carbonate were added and then, 9.1 mg of N,N-dimethylhydrazine solved in 2.3 ml of toluene and 577 mg of dimethyl sulfate were added thereto at 5° C. The mixture was stirred at 5° C. for 24 hours, 3 g of water was added thereto and the organic layer was removed. The aqueous layer was extracted with 3.5 ml of toluene two times. The organic layers were combined and concentrated under reduced pressure to give 1.037 g of a mixture (19:1 (GC area %)) of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5) and methyl 2-(2,6-diethyl-4-methylphenyl)-2-oxo-N-(phenylmethylidene)ethanehydrazonate (x-1).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C@@H:9]([NH2:18])[C@@H:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH3:8][CH:9]([NH:18][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:17]
Reactant: O=C1C=CC(=O)O1
Reactant: C[C@@H](N)[C@@H](O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(NC(=O)/C=C\C(=O)O)C(O)c1ccccc1
Temperature: 50 °C

Procedure:
32.6 grams of maleic anhydride were dissolved in 600 ml of toluene and there were dropped into this solution under stirring a 50° C. warm solution of 50.0 grams of (+)-norephedrine in 100 ml of toluene. Then stirring was continued for 30 more minutes at this temperature. The product was allowed to cool, filtered off with suction, dried and recrystallized from ethyl acetate. Yield: 63.5 grams=77.0% of theory. M.P. 154°-156°
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([OH:25])=O)[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15]C=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].C[N:59](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:25])[C:13]2[N:59]=[CH:15][CH:16]=[CH:17][C:18]=2[C:19](=[O:21])[N:20]=1
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2ccccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.3 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C1) (115 mg, 1 equiv), ethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B2) (150 mg, 1 equiv), HATU (151 mg, 1.2 equiv), DMF (2.7 ml) and DIPEA (0.17 ml, 3 equiv) was shaken at room temperature for 5 h. The reaction mixture was partitioned between ethyl acetate/methanol and aqueous sodium bicarbonate, then the organic layer was brine-washed and dried. Flash chromatography (silica, 3-4% methanol in DCM) gave ethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate as a white solid (190 mg).
Reaction SMILES: [CH:1]([OH:3])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][N:43]2[C:51]3[C:46](=[C:47]([O:52][CH3:53])[CH:48]=[CH:49][CH:50]=3)[C:45]([NH:54][S:55]([C:58]3[S:59][C:60]([Cl:63])=[CH:61][CH:62]=3)(=[O:57])=[O:56])=[N:44]2)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C>[Cl:63][C:60]1[S:59][C:58]([S:55]([NH:54][C:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][C:47]=3[O:52][CH3:53])[N:43]([CH2:42][C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][CH:1]=[O:3])[CH:37]=3)[N:44]=2)(=[O:56])=[O:57])=[CH:62][CH:61]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: O=CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To a solution of formic acid (5 μL, 0.13 mmol) in dry DMF (0.3 mL) was added TBTU (34.7 mg, 0.108 mmol) followed with triethylamine (50.2 μl, 0.360 mmol). This mixture was stirred at room temperature for about 10 min before adding N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (45 mg, 0.09 mmol). The resultant pale yellow mixture was stirred at room temperature overnight. LCMS showed very little reaction, so more acid (˜0.25 mL), followed with TBTU (˜30 mg) were added. This addition was repeated 3 more times over 20 h until by LCMS analysis, there was more product than SM. The reaction mixture was partitioned between ethylacetate (2 mL) and saturated sodium bicarbonate solution (2 mL). The aqueous was extracted with ethyl acetate (×2). The combined organic solutions were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to leave a pale oil which crystallised on standing. This was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by Mass Directed AutoPrep on supelcosil ABZ+Plus column eluting with a gradient of MeCN-Water (95:5+0.05% Formic acid)-Water (+0.1% Formic acid). The solvent was evaporated in vacuo to give the title compound (15.9 mg, 36%) as a pale yellow powder: LCMS (System A) RT=1.02 min, ES+ve m/z 491/493 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1.Cl>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(O)(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 2 h

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid is dissolved in 5 ml. of acetic acid. 1 ml. of concentrated hydrochloric acid is added and the mixture is allowed to stand for 2 hours at 20° and poured onto ice. After the customary work up, 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid, m.p. 193°-195°, is obtained.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[CH3:28][C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>O1CCOCC1.[Cu](I)I.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>[OH:33][C:29]([CH3:30])([CH3:28])[C:31]#[C:32][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
50 mg (0.26 mmol) of copper iodide, 69 mg (0.68 mmol) of triethylamine and 37 mg (0.05 mmol) of dichlorobis(triphenylphosphine)-palladium (II) are added to a suspension of 200 mg (0.52 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 5 ml of anhydrous dioxan, then this mixture is degassed under argon. After 15 minutes, 66 mg (0.78 mmol) of 2-methyl-but-3-yn-2-ol are added, then the mixture is heated at 100° C. for 1 hour. The raw reaction product is then filtered on celite, the filtrate is evaporated to dryness and the residue is purified by chromatography on silica (ethyl acetate), then the product is triturated in methanol to give 135 mg (76%) of 8-(3-hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:14]([CH2:15][C:16](O)=[O:17])[C:13]2[N:12]=[CH:11][CH:10]=[C:9]([Cl:19])[C:8]=2[CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O>[Cl:19][C:9]1[C:8]2[CH2:7][CH2:6][N:5]3[C:3](=[O:4])[CH2:2][NH:1][C:16](=[O:17])[CH2:15][CH:14]3[C:13]=2[N:12]=[CH:11][CH:10]=1
Reactant: NCC(=O)N1CCc2c(Cl)ccnc2C1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CC2c3nccc(Cl)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
94-9. To a stirred solution of 2-(7-(2-aminoacetyl)-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)acetic acid (HCl-salt) (450 mg, 1.41 mmol) and triethylamine (1.17 mL, 8.43 mmol) in DCM (20 mL), T3P (1.25 mL, 2.11 mmol, 50% m/m in AcOEt) was added slowly and the suspension was stirred at RT for 1 h. Saturated aqueous NaHCO3 solution was added and the mixture was extracted with DCM (2×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera One, eluent: gradient from 2% MeOH in AcOEt to 15% MeOH in AcOEt in 18 min) to yield the title compound as a beige solid (66 mg). UPLC-MS: MS 266.1 (M+H+); UPLC rt 0.57 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH2:13]([OH:16])[CH2:14][CH3:15].CCN(CC)CC.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[O:16][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CCCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCOC(=O)Nc1cccc(N)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 3-aminophenylcarbamic acid, propyl ester to generate the title compound. The 3-aminophenylcarbamic acid, propyl ester was prepared by sequentially treating commercial 3-nitrophenyl isocyanate with PrOH containing Et3N at 80° C. for 12 hours followed by reduction with Na2S2O4 in THF/H2O at 100° C.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>COCCOCCOC>[NH:10]([C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CSc1nccc(O)n1
Reactant: Nc1ccccc1
Solvent: COCCOCCOC
Product: Oc1ccnc(Nc2ccccc2)n1
Temperature: 160 °C
Yield: 69.2 %

Procedure:
2-Methylthio-4-hydroxypyrimidine (1.42 g, 10 mmol) was dissolved in 2-methoxyethylether (10 ml). To this solution was added aniline (910 μl, 10 mmol) and the reaction mixture heated at 160° C. for 18 hours. The resulting precipitate was filtered off and washed with diethyl ether (10 ml), water (10 ml), diethyl ether (2×10 ml) and dried under vacuum to give the title product as a colourless solid (1.296 g, 69%). NMR (300 MHz): 5.79, (d, 1H), 6.99 (t, 1H), 7.24 (m, 2H), 7.57 (m, 2H), 7.73 (m, 1H), 8.80 (br, 1H); m/z: (ES+) 188.1 (MH+).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][CH:5]=1.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[CH2:16][C:17]#[N:18].O>C(O)(C)(C)C>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[CH:16]([C:3]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:12])[C:17]#[N:18]
Reactant: COC(=O)c1ccc(OC)nc1
Reactant: N#CCc1ccc(Cl)cc1Cl
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)C(C#N)c2ccc(Cl)cc2Cl)cn1
Temperature: 100 °C
Yield: 29.3 %

Procedure:
To a suspension of potassium-tert-butylate (2.052 g) in tert-butanol (25 ml) was added methyl-6-methoxynicotinate (2.5 g). 2,4-Dichlorobenzyl cyanide (2.782 g) was added portion wise. The mixture was heated to 100° C. for 1.5 h. After cooling to room temperature, water (100 ml) was added and the mixture was washed with diethyl ether. The aqueous phase was neutralized with concentrated aqueous HCl and extracted with EtOAc. The organic phase was washed with water and with brine, dried (MgSO4), filtered and concentrated to dryness to give the title compound (1.407 g) as a yellow foam that was used in the next step without further purification. MS (m/e)=321.0 [M+H+].