Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[O:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[S:2]([O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[O:16])=[CH:9][CH:8]=1)([CH3:1])(=[O:4])=[O:3]
Reactant: O=C1CCc2ccc(O)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2c(c1)C(=O)CC2
Yield: 99 %

Procedure:
12.6 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 12.0 g of 6-hydroxy-1-indanone and 45.2 ml of triethylamine in 350 ml of dichloro-methane and the solution was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 200 ml of dichloromethane, washed twice with 150 ml of saturated sodium hydrogen carbonate solution each time an the combined aqueous phases were extracted once with 100 ml of dichloromethane. The combined organic phases were washed with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. 18.3 g (99%) of 6-mesyloxy-1-indanone were obtained as a brown solid which was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.9 g (18.0 mmol) of 3-bromo-4-hydroxybenzoic acid in 20 mL of 3:1 v/v CH2Cl2/CH3OH was treated with 10.8 mL of 2.0 M (trimethylsilyl)diazomethane solution in hexanes. The mixture was stirred at rt for 2 h, then concentrated to give 4.6 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 3.90 (s, 3H), 5.93 (bs, 1H), 7.05 (d, J=8.5, 1H), 7.92 (dd, J=2.1, 8.5, 1M), 8.19 (d, J=2.0, 1H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[C:12]([CH3:17])([CH3:16])[C:13](Br)=[O:14]>C(Cl)Cl>[CH3:16][CH:12]1[CH2:17][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:13]1=[O:14]
Reactant: c1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2ccccc2C1=O
Reaction time: 2 h

Procedure:
17.3 g (125 mmol) of AlCl3 were added to a solution of 3.91 g (50 mmol) of benzene in 30 ml of analytical grade methylene chloride, while cooling with ice. 11.9 g (52 mmol) of 2-bromoisobutyryl bromide were then added, and stirring was continued at 0° C. for 1 hour and at room temperature for 2 hours. The mixture was heated under reflux for a further 15 hours and then worked up analogously to Example A. The crude product was chromatographed on 100 g of silica gel (hexane/methylene chloride 1:1). The yield was 5.1 g (70%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Cl[CH2:10][CH2:11][OH:12].[OH-].[Na+]>>[OH:12][CH2:11][CH2:10][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: OCCCl
Reactant: Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(OCCO)cc1

Procedure:
p-Cresol may be reacted with excess 2-chloroethanol in the presence of sodium hydroxide to give 4-(2-hydroxyethoxy)toluene which may be purified by conventional techniques.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I-:13].[Na+].II.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[I:13][C:4]1[C:3]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([CH3:1])[NH:6][N:5]=1
Reactant: [I-]
Reactant: Cc1[nH]ncc1-c1ccccc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]nc(I)c1-c1ccccc1
Yield: 27.8 %

Procedure:
To a solution of 5-methyl-4-phenyl-1H-pyrazole (5.0 g, 31.6 mmol) in THF (40 mL) and water (40 mL) were added sodium iodide (4.74 g, 31.6 mmol), iodine (12.03 g, 47.4 mmol), and K2CO3 (4.37 g, 31.6 mmol) at room temperature. The reaction was refluxed for 2 h and then quenched with aqueous Na2SO3 (10%). The mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (2.5 g). LCMS m/z=284.7 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H), 7.24-7.54 (m, 5H), 13.13 (s, 1H).
Reaction SMILES: C([C:3]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)C.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH2:21]1[O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:10]3[CH:11]=[CH:3][C:4]([C:5]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[O:7])=[CH:8][CH:9]=3)=[CH:15][C:16]=2[O:22]1
Reactant: CCc1cc(OCc2ccc3c(c2)OCO3)ccc1C(=O)O
Reactant: Nc1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccncc1)c1ccc(OCc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 18-4 (0.545 g, 2 mmol) was added 4-aminopyridine 18-5 (0.235 g, 2.5 mmol), 1-hydroxy-benzotriazole hydrate (0.338 g, 2.5 mmol), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (0.479 g, 2.5 mmol) and dry DMF (5 ml) followed by triethylamine (0.35 ml, 2.5 mmol). The mixture was stirred at ambient temperature overnight. Then the DMF was removed under high vacuum. The residual oil was chromatographed on silica gel to obtain a white solid 18-6.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([C@H:18]2[CH2:23][CH2:22][C:21](=[O:24])[N:20]([C@@H:25]([CH:33]3[CH2:35][CH2:34]3)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:19]2[C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH:15]=[CH:16][CH:17]=1.[CH2:43](Br)[CH:44]=[CH2:45]>C1COCC1>[CH2:45]([C@H:22]1[CH2:23][C@H:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)[C@@H:19]([C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)[N:20]([C@@H:25]([CH:33]2[CH2:35][CH2:34]2)[C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[C:21]1=[O:24])[CH:44]=[CH2:43]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)[C@H](C1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C(=O)OC(C)(C)C)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1M in THF, 0.165 mL, 0.165 mmol) was added dropwise at −78° C. to a solution of (S)-tert-butyl 2-(2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-cyclopropylacetate (Example 249, Step C, 71 mg, 0.15 mmol) and allyl bromide (15.54 uL, 0.165 mmol) in 0.5 mL of THF. The reaction was allowed to warm to ambient temperature. After stirring for 2 h, the reaction was quenched with sat. aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl solution and dried over sodium sulfate, then filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with ethyl acetate/hexane provided the title compound.
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C1CCCCCCCCCCC=1.[OH2:29]>>[CH:5]1([OH:29])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C1CCCCCCCCCCC1
Reactant: O
Agent: C1=CCCCCCCCCCC1
Solvent: ClC(Cl)Cl
Product: OC1CCCCCCCCCCC1
Yield: 93 %

Procedure:
The chloroform layer (top layer) was diluted at 5° C. with 200 ml of water and then passed to the heated hydrolysis vessel where chloroform was distilled off. Next, the reaction mixture was heated at 95°-100° C. in this vessel for 60 minutes. The organic layer was separated off and analyzed. It was found to contain 3.52 grams of cyclododecane, 6.80 grams of cyclododecene (conversion 77%) and 23.45 grams of cyclododecanol (0.121 mole; yield 93%, calculated with subtraction of recovered starting material).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O.CN(C=O)C>O1CCOCC1>[Cl:16][C:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=2[S:9](=[O:12])(=[O:11])[N:8]=1
Reactant: O=C1NS(=O)(=O)c2c(F)cccc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=S1(=O)N=C(Cl)c2cccc(F)c21

Procedure:
3.02 g of 7-fluoro-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (EP291851 A2 19881123), 1.64 ml of thionyl chloride and a catalytic amount of DMF in 13 ml of dioxane are heated under reflux for 45 hours. The mixture is concentrated and the residue is crystallized in toluene. 2.50 g of a crude solid is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:19]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH2:8][C@@H:7]1[CH3:39])=[O:5])[CH3:2].[C:40]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:41]=1.C(O)C.CN1CCNCC1NC(N=NC(NC1CNCCN1C)=O)=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:40][CH3:41])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:19]([CH2:24][C:25]2[CH:26]=[C:27]([C:35]([F:36])([F:38])[F:37])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=2)[C:20]([O:22][CH3:23])=[O:21])[CH2:8][C@@H:7]1[CH3:39])=[O:5])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)N1c2cc(OC)c(O)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: CN1CCNCC1NC(=O)N=NC(=O)NC1CNCCN1C
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc(OC)c(OCC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 63.7 %

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-hydroxy-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (30 mg, 0.053 mmol), triphenylphosphine (28 mg, 0.11 mmol), ethanol (16 μL, 0.79 mmol), and bis-(N-methylpiperazinyl)-azodicarboxamide (30 mg, 0.11 mmol) in benzene (1 mL) was stirred at room temperature for 12 hours. Purification of the solution directly by silica gel chromatography using 0-20% ethyl acetate/hexanes as eluent afforded 20 mg of the title compound (67%): MS m/z 593 (M+), 610 (M++17); 1H NMR (CDCl3) δ6.39 (C5, s, 1H), 1.17 (C2-Me, d, 3H, J=6.2 Hz).
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1C=CC=CC=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[CH2:29])=[CH:26][CH:25]=1>C(N(CC)CC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:28]([C:27]3[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:29][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)C1
Reaction time: 1 h

Procedure:
The compound of Example 6 (5.0 gm) was heated in refluxing benzene (30 ml) containing 4-chlorostyrene (7.0 ml). Addition of a benzene (10 ml) solution of triethylamine(7.5 ml) was followed by one hour of continued heating. The cooled mixture was filtered, rotovapped, and dried on the vacuum pump to remove excess styrene. The residual solid was recrystallized from hexane/benzene (charcoal) to give the title compound (6.3 gm); m.p.: 128° to 130° C. NMR (CDCl3) 7.3-6.9 (m, 8H, ArH), 5.4 (dd, 1H, CH), 4.3 (q, 2H, OCH2), 3.8 (m, 1H, CH), 3.0 (m, 1H, CH), 1.38 (t, 3H, CH3).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19](=O)[CH:20]=[CH:21]N(C)C.C(=O)(O)[O-].[Na+].ClCCl.CCCCCC>C(O)(=O)C.ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]1[N:4]2[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]2[N:2]=[CH:21][CH:20]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: NC(=O)c1ncn2c(-c3cc(Cl)ccc3Cl)ccnc12
Yield: 74.3 %

Procedure:
A stirred mixture of 5.2 g of 4-amino-5-imidazolecarboxamide hydrochloride and 10.0 g of 2',5'-dichloro-3-dimethylaminoacrylophenone (prepared as described in Example 4) in 80 ml of glacial acetic acid was heated at reflux for 4 hours. Evaporation in vacuo gave a dark oil which was dissolved in dichloromethane and treated with saturated sodium bicarbonate. The organic layer was separated, washed with water then dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of hydrous magnesium silicate. Evaporation of the eluate gave a semi-solid which was treated with hot dichloromethane-hexane to give a yellow precipitate which was collected by filtration and dried to give 7.3 g of the product of the example, mp 230°-234° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1>[Pd].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Cc1cnc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cnc(N)c(N)c1
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A mixture of 38 (790 mg, 5.17 mmol), methanol (60 mL), and 5% Pd-C (70 mg) was shaken under H2 (20-30 psi) for 3 h, then filtered and evaporated to give 629 mg (99%) of the diamine 39 as a black thick oil. 1H NMR (CDCl3) δ 2.160 (s, 3H), 3.308 (bs, 2H), 4.160 (bs, 2H), 6.740 (s, 1H), 7.459 (s, 1H). It was used for the next reaction without further purification.
Reaction SMILES: C[Si](C)(C)[N:3]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[Si](C)(C)C.[CH3:15][N:16]([CH2:18][CH2:19][NH:20][C:21]([CH3:26])=[CH:22][C:23](=O)[CH3:24])[CH3:17].FC(F)(F)C(F)(F)C(O)=O.CC(C)([O-])C.[Na+]>O1CCCC1>[CH3:11][N:10]([CH2:9][CH2:8][NH:3][C:23](=[CH:22][C:21](=[N:20][CH2:19][CH2:18][N:16]([CH3:15])[CH3:17])[CH3:26])[CH3:24])[CH3:12]
Reactant: CC(=O)C=C(C)NCCN(C)C
Reactant: CN(C)CCN([Si](C)(C)C)[Si](C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=C(O)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=CC(C)=NCCN(C)C)NCCN(C)C
Reaction time: 1 h

Procedure:
3.48 g (0.015 moles) of N,N-Bis(trimethylsilyl)-2-(N′,N′-dimethylamino)ethylamine were mixed with 1.7 g (0.01 moles) of 4-(2-(N,N-dimethylamino)ethylamino)-3-penten-2-one. To this mixture was added 1.64 g (0.0125 moles) of pentafluoropropionic acid dropwise over 5 minutes with rapid stirring. The mixture darkened and became warm, eventually forming two immiscible layers, and was allowed to stir for 1 hour. 0.98 g (0.0125 moles) of sodium t-butoxide dissolved in 5 ml of tetrahydrofuran was then added dropwise over a five minute period. The mixture warmed and became one liquid phase, which was yellow. The solvent was then removed by vacuum distillation at room temperature, and the product then vacuum distilled out of the resulting residue as a clear liquid by heating >150° C. Yield of MeC(NCH2CH2NMe2)CHC(HNCH2CH2NMe2)Me=2.05 g (85% of theoretical).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([C:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[CH:10].C(NC(C)C)(C)C.C1(C)C=CC=CC=1>C1COCC1.[Pt]=O.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.[Cu](I)I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:10][CH2:9][C:11]2([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: C#CC1(N)CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: NC1(CCc2ccc(F)cc2)CCCCC1

Procedure:
2.5 g (11.3 mmol) 1-fluoro-4-iodo-benzene, 1.5 g (11.9 mmol) 1-ethynyl-cyclohexylamine, 793 mg (1.13 mmol) PdCl2(PPh3)2, 67 mg (0.35 mmol) copper iodide and 50 mL diisopropylamine are stirred for 2 hours at 70° C. Then the base is distilled off and the residue is combined with ethyl acetate. The insoluble constituents are filtered off and the filtrate is evaporated down. The alkyne thus prepared is dissolved in 35 mL THF and 35 mL toluene and hydrogenated with platinum oxide as catalyst at normal pressure. The catalyst is separated off and the filtrate is freed from the solvent. The crude product is dissolved in ethyl acetate and combined with 10% hydrochloric acid in ethyl acetate. The precipitated solid is filtered off and washed with ethyl acetate. Yield: 1.3 g (45%; hydrochloride); mass spectroscopy: [M+H]+=222.
Reaction SMILES: CO.[OH-].[Na+:4].[C:5]1([C:11]2[CH:12]=[C:13]([C:17]([NH:19][C:20]3[CH:28]=[C:27]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)[CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[O:18])[CH:14]=[N:15][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCOCC1>[C:5]1([C:11]2[CH:12]=[C:13]([C:17]([NH:19][C:20]3[CH:28]=[C:27]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)[CH:26]=[CH:25][C:21]=3[C:22]([O-:24])=[O:23])=[O:18])[CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[Na+:4]
Reactant: O=C(Nc1cc(-n2cccn2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1cc(-n2cccn2)ccc1C(=O)[O-])c1cncc(-c2ccccc2)c1

Procedure:
Methanol (2 mL), dioxane (2 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.083 mL) were added to the obtained 2-(5-phenylpyridine-3-carboxamido)-4-(1H-pyrazol-1-yl)-benzoic acid (53 mg), and the solvent was evaporated under reduced pressure. Water and acetone were added to the obtained residue, and the solid substance was collected by filtration to obtain 23 mg of sodium 2-(5-phenylpyridine-3-carboxamido)-4-(1H-pyrazol-1-yl)benzoate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH2:11][C:12]#[N:13].O.[NH2:16][NH2:17]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[NH:17][N:16]=[C:12]([NH2:13])[CH:11]=1
Reactant: COc1ccc(C(=O)CC#N)c(F)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(N)n[nH]2)c(F)c1
Yield: 88.6 %

Procedure:
To 3-(2-Fluoro-4-methoxyphenyl)-3-oxopropanenitrile (9.55 g, 49.4 mmol) suspended in ethanol (165 mL) was added hydrazine hydrate (1.743 g, 54.38 mmol). The resulting mixture was heated at reflux overnight. Then, the organic solvent was evaporated in vacuo and the resulting residue was chromatographed (eluting with 9:1 methylene chloride:methanol) to give 9.07 g (88% yield) of the title compound. LCMS (ESI): calc.=207; obs. M+H=208.2.
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[S:10]/[C:9](=[N:11]\[C:12](=[O:22])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])/[N:8]([CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:7]=1[CH3:30])(=[O:5])[CH3:4]>O1CCCC1>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH3:21])=[C:13]([CH:18]=1)[C:12](/[N:11]=[C:9]1\[S:10][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[C:7]([CH3:30])[N:8]\1[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)=[O:22]
Reactant: [Li]C
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)=O)c(C)n1CC1CCCCO1
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)O)c(C)n1CC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of methyllithium (Aldrich, 1.6 M in diethyl ether, 0.41 mL, 0.66 mmol) was added slowly a solution of Example 253 (0.14 g, 0.33 mmol) in tetrahydrofuran (3 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes and was allowed to reach room temperature. The reaction mixture was quenched with water (6 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-5% methanol in CH2Cl2) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.21-1.36 (m, 1H), 1.41-1.48 (m, 3H), 1.49 (s, 3H) 1.50 (s, 3H), 1.57-1.67 (m, 1H), 1.74-1.85 (m, 1H), 2.42 (s, 3H), 3.68-3.89 (m, 3H), 3.79 (s, 3H), 3.92-4.09 (m, 1H), 4.17-4.38 (m, 1H), 5.60 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.7 Hz, 1H), 7.68 (d, J=2.7 Hz, 1H); MS (ESI+) m/z 439 (M+H)+; Anal. Calculated for C21H27ClN2O4S: C, 57.46; H, 6.20; N, 6.38. Found: C, 57.44; H, 5.88; N, 6.06.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30](F)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CN1CCNCC1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)c(Cl)c2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)c(Cl)c2)CC1
Yield: 85.3 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.12 mL, 1 mmol), triethylamine (0.14 mL, 1 mmol) and 1-(3-chloro-4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example D-1, 0.14 g, 0.32 mmol) provided 0.14 g of the title compound as a solid.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]>C(OCC)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[CH3:1]
Reactant: [Li]C
Reactant: Cc1cc([N+](=O)[O-])ccc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1cc([N+](=O)[O-])ccc1C(C)O
Yield: 89.8 %

Procedure:
Following the General Procedure of Description 8, MeTiCl3 was freshly prepared prior to use from commercial titanium tetrachloride (TiCl4) (4.73 mL, 8.17 g, 43.1 mmol) and methyl lithium (MeLi) (1.6 M in Et2O, 26.9 mL, 43.0 mmol) in anhydrous diethyl ether (Et2O) (230 mL). A solution of 2-methyl-4-nitro-benzaldehyde (7b) (7.11 g, 43.0 mmol) in anhydrous Et2O (200 mL) was added. Aqueous work-up afforded 7.0 g (90% yield) of the target compound (7c) as a yellow solid. The material was of sufficient purity to be used directly in the next step without further isolation and purification procedures. Rf: ˜0.24 (EtOAc/Hxn=1:2 v/v). 1H NMR (300 MHz, CDCl3): δ 8.07 (dd, J=8.7, 2.7 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 5.18 (q, J=6.6 Hz, 1H), 2.42, (s, 3H), 1.92-1.88 (br. m, 1H), 1.47 (d, J=6.3 Hz, 3H) ppm.