Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[C:23]=[O:24])[CH:17]=1.CCCCCC>C1COCC1>[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([O:7][CH2:6][CH3:5])=[O:24])[CH:17]=1.[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([O:7][CH2:6][CH3:5])=[O:24])[CH:17]=1.[CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7]
Reactant: Cc1cccc(N=C=O)c1
Agent: OCC#CC#CCO
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 500 ml 3-necked round bottom flask was fitted with a magnetic stirrer, an addition funnel and a thermometer. To the flask was added 11.0 grams (0.1 mole) of 2,4-hexadiyn-1,6-diol in 300 ml of THF, 0.5 g of di-t-butyltin-di-2-ethoxyhexanoate and 2 ml. of triethylamine. The resultant solution was stirred and 39.9 g (0.3 mole) of m-tolyl isocyanate was added dropwise over a period of half an hour. The reaction temperature was maintained at about 25° C. by a cold water bath. The reaction was allowed to proceed for 2 hours. Into the resultant solution about 1500 ml of hexane was poured. The precipitate was collected and dried under vacuum. The yield of the crude material was quantitative. Elemental and infrared analysis was conducted on a sample recrystallized from acetone-hexane, which was in the inactive form. The m.p. was 133° C. Analytical: Calculated for C,H,N,O: 70.21; 5.32; 7.45; 17.02. Found for C,H,N,O: 70.17; 5.20; 7.12; 17.21. Infrared spectrum (KBr Pellet):
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:32].[Li+].[Br:34][C:35]1[C:47]2[S:46][C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[C:43]=2[C:42]([C:52]2[CH:57]=[C:56]([Br:58])[C:55]([O:59][C@@H:60]([CH2:68]O)[CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[C:54]([Br:70])[CH:53]=2)=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[CH:40]2>C1COCC1>[Br:34][C:35]1[C:47]2[S:46][C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[C:43]=2[C:42]([C:52]2[CH:53]=[C:54]([Br:70])[C:55]([O:59][C@@H:60]([CH2:68][Br:32])[CH2:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[C:56]([Br:58])[CH:57]=2)=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[CH:40]2
Reactant: OC[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: [Br-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrC[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
Diethylazodicarboxylate (0.151 mL, 0.96 mmol) was added dropwise to a 0° C., stirred solution of triphenylphosphine (0.257 g, 0.98 mmol) in THF (6 mL) under a dry nitrogen atmosphere. After 20 min., lithium bromide was added to a nearly colorless reation mixture, followed by adding a solution of (R)-6-bromo-1 1-[3,5-dibromo-4-(1-hydroxymethyl-2-phenyl-ethoxy)-phenyl]-benzo[b]naphtho[2,3-d]thiophene (0.273 g, 0.392 mmol) in THF (3 mL). After 1 h, the solution was allowed to warm to ambient temperature. After 2 h, the reaction mixture was quenched with water (0.2 mL) and further diluted with ethyl ether (50 mL). Silica gel (8 mL) was added. Solvent was removed and the silica adsorbate was flash chromatographed (eluent 98:2 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.23 g, 73%): mp >90° C. (dec.): MS (EI): [M+], 4 bromine isotope pattern, 756, 758, 760, 762, 764; Anal. Calc. for C28H17Br3N203S.0.25 hexane: C, 49.97, H, 2.97, N, 0.00. Found: C, 49.97, H, 2.83, N, 0.02.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cccnc1F
Reactant: NCc1ccccc1
Product: N#Cc1cccnc1NCc1ccccc1
Yield: 66 %

Procedure:
Prepared in 66% yield from 2-fluoronicotinonitrile and benzylamine according to the procedure described for Example 178A. MS (ESI+) m/z 210.0 (M+H)+; 1H NMR (DMSO-d6) δ 4.59 (d, J=6.1 Hz, 2H), 6.64 (dd, J=7.6, 4.9 HZ, 1H), 7.16-7.24 (m, 1H), 7.26-7.32 (m, 5H), 7.71 (dd, J=5.9, 5.9 Hz, 1H), 7.91 (dd, J=7.6, 1.9 Hz, 1H), 8.23 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH3:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36]O>C(Cl)Cl>[I:25][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:28][CH3:27]
Reactant: II
Reactant: COCc1ccccc1CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1ccccc1CI
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of imidazole (338 mg, 4.98 mmol) and triphenylphosphine (1.3 g, 4.98 mmol) in methylene chloride (10 mL) is added iodine (1.26 g, 4.98 mmol) in portions. The mixture is stirred at RT for 45 min then a solution of (2-methoxymethylphenyl)-methanol (630 mg, 4.14 mmol) in methylene chloride (3 mL) is added dropwise and stirring is continued for 3 h. The mixture is concentrated and the insoluble material is filtered. The filtrate is evaporated and the residue is purified by column chromatography using a gradient of 0-50% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:23][C@@H:24]2[O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])=[CH:19][CH:18]=3)[CH2:15][CH2:14]1)[CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:68][C:69]([O:74][CH:75]1[CH2:80][CH2:79][CH2:78][CH2:77][O:76]1)([CH3:73])[CH2:70][CH:71]=[O:72].[Cl-].[NH4+]>O1CCCC1.C(OCC)C.CCCCCC>[Si:33]([O:32][C@@H:24]1[C@@:25]2([CH3:26])[C:20](=[CH:19][CH:18]=[C:17]3[C@@H:27]2[CH2:28][CH2:29][C@@:30]2([CH3:31])[C@H:16]3[CH2:15][CH2:14][C@@H:13]2[C@H:2]([CH3:1])[CH:3]([S:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH:71]([OH:72])[CH2:70][C:69]([O:74][CH:75]2[CH2:80][CH2:79][CH2:78][CH2:77][O:76]2)([CH3:73])[CH3:68])[CH2:21][C@@H:22]([O:40][Si:41]([C:44]([CH3:46])([CH3:45])[CH3:47])([CH3:42])[CH3:43])[CH2:23]1)([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34]
Reactant: CC(C)(CC=O)OC1CCCCO1
Reactant: CC(CS(=O)(=O)c1ccccc1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@H](C(C(O)CC(C)(C)OC1CCCCO1)S(=O)(=O)c1ccccc1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
In 2 ml of tetrahydrofuran was dissolved 71 mg of 20-methyl-1α,3β-bis(t-butyldimethylsilyloxy)-21-phenylsulfonylpregna-5,7-diene and the solution was cooled in a dry ice-acetone bath under argon atmosphere. To the solution was added a 0.4-ml portion of a lithium diisopropylamide solution prepared from 2 ml of a 1.5N hexane solution of butyllithium and 0.5 ml of diisopropylamine in 10 ml of tetrahydrofuran. The resulting mixture was stirred at -30° C. for 30 minutes. The mixutre was again cooled in a dry ice-acetone bath, a solution of 120 mg of 3-methyl-3-(2-tetrahydropyranyloxy)butanal in 1 ml of tetrahydrofuran was added, and the resulting mixture was stirred at -50° C. for 5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was allowed to warm to ambient temperature. Diethyl ether was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layer was combined, washed in sequence with an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride, then dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 68 mg of 1α,3β-bis(t-butyldimethylsilyloxy)-22-phenylsulfonyl-25-(2 -tetrahydropyranyloxy)cholesta-5,7-dien-23-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[C:29]([C:31]([NH:33]O)=[NH:32])[CH:28]=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:22][N:33]=[C:31]([C:29]5[CH:28]=[CH:27][N:26]=[C:25]([NH2:24])[CH:30]=5)[N:32]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1ccnc(N)c1
Product: Nc1cc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)ccn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) (171 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyridine-4-carboxamidine (example B.6) (114 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (dichloromethane/hexane) as a yellow solid (112 mg, 49%). MS (EI) 457.1 [(M)+]; mp 252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:16]C)C(C#N)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Br.[OH-].[Na+].CCCCCC.[C:27]([O:30]CC)(=[O:29])[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:16])[C:28]([C:27]([OH:30])=[O:29])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COc1cc(-c2cccc(Cl)c2)cnc1C#N
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(O)c1ncc(-c2cccc(Cl)c2)cc1O
Reaction time: 3 h

Procedure:
To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser was charged 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine, 2, (1 g, 4 mmol) and a 48% aqueous solution of HBr (10 mL). While being stirred, the reaction solution was heated to reflux for 20 hours. The reaction was determined to be complete due to the disappearance of 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction contents was then cooled to 0° C. to 5° C. with stirring and the pH was adjusted to approximately 2 by the slow addition of 50% aqueous NaOH. Stirring was then continued at 0° C. to 5° C. for 3 hours. The resulting solid was collected by filtration and washed with water, then hexane. The resulting cake was dried in vacuo at 40° C. to afford 1.03 g (quantitative yield) of the desired product as an off-white solid. 1H NMR (DMSO-d6) δ 8.52 (d, 1H), 7.99 (d, 1H), 7.95 (s, 1H) 7.81 (t, 1H), 7.57 (s, 1H), and 7.55 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(O)C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Yield: 73.6 %

Procedure:
A solution of 1.50 g (5.14 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxymethyl-phenyl)-piperidine-1-carboxylate, 1.73 g (6.16 mmol) of triphenylchloromethane and 674 mg (6.68 mmol) of triethylamine in 20 ml of methylene chloride was stirred at room temperature for 5 hours. For the working-up, the reaction mixture was washed with 10 ml of water and 10 ml of saturated sodium hydrogen carbonate solution, the organic phase was dried over sodium sulphate and evaporated under reduced pressure. The crude product was chromatographed on silica gel using a 95:5 mixture of toluene and ethyl acetate as the eluent. There were obtained 2.08 g (77.5% of theory) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate as a colourless foam; MS: 567 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@H:5]([CH3:17])[CH2:6][C@H:7]([NH:9]C(OC(C)(C)C)=O)[CH3:8])[CH3:2].[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[CH2:1]([O:3][C:4](=[O:18])[C@H:5]([CH3:17])[CH2:6][C@H:7]([NH2:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)[C@H](C)C[C@@H](C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](C)C[C@@H](C)N
Reaction time: 0.17 h

Procedure:
Next, (2R,4R)-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid ethyl ester (142 mg, 0.548 mmol) is added to trifluoroacetic acid (5 mL). After 10 minutes, the solvent is removed under reduced pressure. Methylene chloride is added and the solvent is removed under reduced pressure to give (2R,4R)-4-amino-2-methyl-pentanoic acid ethyl ester trifluoroacetate. This material is used directly in the subsequent coupling reaction.
Reaction SMILES: [Li]CCCC.[Br-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:37]1([C:43]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:44]2[CH:48]=[C:47]([CH:49]=O)[N:46]=[CH:45]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[CH:49]([C:47]1[N:46]=[CH:45][N:44]([C:43]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:48]=1)=[CH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of n-BuLi (4.1 mL, 6.5 mmol, 1.6M in hexanes) was added dropwise to a suspension of n-undecyl-triphenylphosphonium bromide (3.09 g, 6.2 mmol, obtained from triphenylphosphine and undecylbromide) in 100 mL THF at -78° C. under an atmosphere of N2. The resulting orange solution was stirred for 45 minutes before a solution of 1-(triphenylmethyl)-4-imidazolecarboxaldehyde (2.0 g, 5.9 mmol, Ref: Kelly J. L., Miller C. A., and McLean E. W., J. Med. Chem. 1977; 20:721) in 75 mL THF was added dropwise. Warmed to room temperature and stirred for 16 hours. Quenched by adding 50 mL saturated NH4Cl solution and concentrating in vacuo. The residue was partitioned between water and dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give a yellow oil. Chromatography (10% EtOAc/hexanes on silica) gave the title compound (1.8 g, 64%) as a clear oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.O>[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([O:31][C:2]3[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=3)=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1csc2cc(O)ccc12
Reactant: CCCCCC(=O)OCc1cc(Cl)ncn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCCC(=O)OCc1cc(Oc2ccc3c(C(=O)OCC)csc3c2)ncn1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A suspension of 984 mg (4.05 mMol) hexanoic acid 6-chloro-pyrimidin-4-ylmethyl ester, 751 mg (3.38 mMol) 6-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester (Step 12.3) and 1.43 g (6.76 mMol) K3PO4 in 20 ml NMP is stirred for 1.5 h at 60° C. The reaction mixture is dissolved in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (SiO2; hexane/EtOAc 4:1→1:1) gives the title compound: MS: [M+1]+=429; TLC(hexane/EtOAc 4:1): Rf=0.14.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH:24]([CH3:27])[CH2:25][OH:26]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH:24]([CH3:27])[CH2:25][OH:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: CC(N)CO
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC(C)CO)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.9 %

Procedure:
A mixture of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (250 mg, 0.82 mmol), rac-2-amino-1-propanol (63 mg, 0.84 mmol) and TBD (29 mg, 0.21 mmol) was stirred for 15 h at room temperature under argon. The reaction mixture was concentrated onto silica then purified by chromatography (silica, 0 to 4% methanol in dichloromethane) to give the title compound (145 mg, 60%) as a white solid after trituration with diisopropyl ether. MS: m/e=348.3 [M+H]+.
Reaction SMILES: CCCCCC.C([Li])CCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1.[Br:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([O:32][CH3:33])=[C:24]([CH:34]=[O:35])[CH:23]=1.[Cl-].[NH4+]>C1COCC1>[S:12]1[C:13]([CH:34]([C:24]2[CH:23]=[C:22]([Br:21])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[O:32][CH3:33])[OH:35])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: c1ccc2sccc2c1
Reactant: COc1c(C=O)cc(Br)c2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C(O)c2cc3ccccc3s2)cc(Br)c2ccccc12
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 6.2 ml, 9.90 mmol) was added dropwise to a solution of benzothiophene (1.33 g, 9.90 mmol) in THF (20 ml) at −78° C. and the reaction mixture was stirred at the same temperature for 10 minutes. To this mixture, a solution of 4-bromo-1-methoxynaphthalene-2-carbaldehyde (2.5 g, 9.43 mmol) in THF (30 ml) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for two hours, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (3.12 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.CC(C)(C)C([O:14][C:15]1[C:20](=[O:21])[N:19]([CH3:22])[CH:18]=[N:17][C:16]=1[C:23](OC)=[O:24])=O.O.C(#N)C>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:23]([C:16]2[N:17]=[CH:18][N:19]([CH3:22])[C:20](=[O:21])[C:15]=2[OH:14])=[O:24])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ncn(C)c(=O)c1OC(=O)C(C)(C)C
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 90 °C

Procedure:
4-Fluorobenzylamine (3 eq.) was added to a solution of the crude product of Step 4 in DMF and the reaction mixture was heated to 90° C. for one hour. The title compound was obtained by RP-HPLC (C18, eluting with water and acetonitrile containing 0.1% TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-].[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1c(C)cc(I)cc1Cl
Reactant: COc1ccc(O)cc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cc(C)c(C(C)=O)c(Cl)c2)cc1
Yield: 19 %

Procedure:
To a solution of 1-(2-chloro-4-iodo-6-methylphenyl)ethanone (1.1 g, 3.7 mmol), K3PO4 (1.6 g, 7.4 mmol), and 4-methoxyphenol (0.55 g, 4.44 mmol) in DMF (55 mL) was added tetrabutylammomium bromide (0.12 g, 0.37 mmol) and copper(I) iodide (70 mg, 0.37 mmol). The reaction was heated at reflux for 22 h. The solution was extracted with EtOAc (10 mL), and the organic layer was separated, washed with H2O (11 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-[2-chloro-4-(4-methoxyphenoxy)-6-methylphenyl]ethanone as yellow oil in 19% yield: 1H NMR (500 MHz, CDCl3) δ 6.97 (m, 2H), 6.90 (m, 2H), 6.73 (d, J=2.19 Hz, 1H), 6.67 (d, J=1.99 Hz, 1H), 3.81 (s, 3H), 2.52 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>C(#N)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: CC#N
Product: Fc1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Temperature: 200 °C
Yield: 97 %

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine (0.25 g, 0.97 mmol) was dissolved in anhydrous acetonitrile (3 mL) and 4-fluorobenzenamine was added (0.10 mL, 1.06 mmol). The mixture was heated at 200° C. for 600 s in a microwave (Emrys Optimizer model, Personal Chemistry). The solvents were removed under vacuum to give the desired product as a beige powder (0.313 g, 97%.). The crude product was used for the subsequent step.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10])[C:3]=1[NH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10])[C:3]=1[NH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.8 %

Procedure:
The product of Example 17, Step A, methyl 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]amino]benzoate (306 mg, 0.84 mmol) was dissolved in ethanol (40 mL), to which was added 1 M NaOH solution (40 mL). This mixture was stirred at room temperature for 15 hours, then poured into 1 M HCl solution (100 mL). The resulting precipitate was extracted with EtOAc (3×80 mL) and the combined EtOAc extracts then combined and washed with water (2×100 mL) and saturated NaCl (100 mL). The organic fraction was dried (Na2SO4), the solvent removed under reduced pressure and the resulting residue purified by column chromatography on flash silica (50% EtOAc/hexanes as eluant) to afford 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]-amino]benzoic acid as a crystalline white solid (168 mg, 57%); m.p. (EtOAc/hexanes) 180–183° C.