Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6]([CH3:12])=[N:7]2.[CH:14]1([NH2:21])[CH2:19][CH2:18][CH2:17][CH:16]([NH2:20])[CH2:15]1>CS(C)=O.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:20][CH:16]1[CH2:17][CH2:18][CH2:19][CH:14]([NH2:21])[CH2:15]1)[C:6]([CH3:12])=[N:7]2
Reactant: NC1CCCC(N)C1
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2cccc(Br)c2nc1NC1CCCC(N)C1
Temperature: 100 °C
Yield: 150.7 %

Procedure:
A mixture of 5-bromo-3-chloro-2-methylquinoxaline (126e, 7.25 g, 28.2 mmol) and (rac)-1,3-cyclohexanediamine (TCI America, Inc., Portland, Oreg.; 23.69 m, 197 mmol) in DMSO (28.2 mL) was heated to 100° C. for 16 h. The reaction was cooled to RT and diluted with water. It was extracted with EtOAc (3×), dried over MgSO4, filtered, and concentrated to give (N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483a, 14.25 g, 151% yield) a dark orange-brown oil. MS (ESI, pos. ion) m/z: 335.0/337.0 (M+1). Separation of (1S,3R)—N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine. The racemic mixture was separated using chiral SFC via two purifications. 1st Purification: Preparative SFC: AY-H (5 μm, 21 mm×25 cm) with 20% organic modifier: 80% carbon dioxide. Organic modifier: methanol with 0.2% diethylamine. F=70 ml/min, T=40° C., BPR=100 bar, P=179 bar, 256 nm. (N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483a, 14.25 g) dissolved in methanol (250 mL, 60 mg/mL). 0.5 mL injection. Two peaks were collected. 2nd Purification: Preparative SFC: Repurification of peak 2. OJ-H (5 μm, 21 mm×25 cm, S/N=0131) with 20% organic modifier modifier: 80% carbon dioxide. Organic modifier: methanol with 0.2% diethylamine. F=70 mL/min, T=40° C., BPR=100 bar, P=172 bar, 256 nm. Peak 2 from the 1st purification was dissolved in methanol (60 mL). 0.6 mL injection. A single peak was collected to give (1S,3R)—N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483b, 2.81 g, 30% recovery) as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (1H, d, J=7.63 Hz) 7.70 (1H, d, J=8.02 Hz) 7.15-7.26 (2H, m) 4.17 (1H, br. s.) 2.76 (1H, t, J=10.17 Hz) 2.52 (3H, br. s.) 2.08 (1H, d, J=12.13 Hz) 1.95 (1H, br. s.) 1.76 (2H, d, J=9.19 Hz) 1.26-1.41 (3H, m) 1.02-1.17 (1H, m). MS (ESI, pos. ion) m/z: 335.0/337.0 (M+1).
Reaction SMILES: F[C:2]([F:17])(S(F)(=O)=O)[C:3](F)(F)[C:4](F)(F)[C:5](F)(F)F.O[C@@H]1C[C@@]2(C)[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][C@H:28]2[CH3:38])=[CH:25][C:24](=[O:39])[CH2:23][CH2:22]1.Cl.O>C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2>[F:17][C@H:2]1[CH2:3][C@@:4]2([CH3:5])[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][C@H:28]2[CH3:38])=[CH:25][C:24](=[O:39])[CH2:23][CH2:22]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@H]2O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reaction time: 1 h

Procedure:
11.5 ml of perfluorobutane-1-sulfonic acid fluoride was added in drops at 0° C. to a solution of 13.08 g of 11α-hydroxy-7α-methyl-estr-4-ene-3,17-dione (produced by means of microbiological synthesis according to the invention [Part A]) in 250 ml of toluene and 18.2 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene. After 1 hour, it was neutralized with 2 M hydrochloric acid, added to water, extracted four times with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. After the crude product was chromatographed on silica gel with a hexane/ethyl acetate gradient, 8.7 g of 11β-fluoro-7α-methyl-estr-4-ene-3,17-dione was obtained. Melting point: 101.4° C., [α]D: +135.8° (CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.C(Cl)Cl.[NH:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1>CN(C=O)C>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:23]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Yield: 178.2 %

Procedure:
A solution of lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate (15.0 g, 70.8 mmol), thionyl chloride (53.1 mL, 106.2 mmol), CH2Cl2 (600 ml), and DMF (6 ml) was heated to reflux. After 3 h the resulting yellow solution was concentrated under reduced pressure, and the residue was suspended in CH2Cl2 (500 mL). (3R)-pyrrolidin-3-ol (2.3 g, 26.2 mmol) was then added dropwise. After 12 h the reaction was quenched with 1N NaOH (500 mL), the layers were separated, and the aqueous layer was extracted with 2×500 mL CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, then concentrated under reduced pressure. The resulting solid was triturated with Et2O then collected by filtration to give a white solid (13.2 g, 70%). MS: 283.2/285.2 (MH+); HPLC Rf: 3.49 min.; HPLC purity: 99%.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]23[CH2:15][N:14]([C:16]4[N:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:13][CH:12]2[CH2:11][S:10][C:9]([NH:22]C(=O)C2C=CC=CC=2)=[N:8]3)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.CON>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[S:6][C:5]([C:7]23[CH2:15][N:14]([C:16]4[N:17]=[CH:18][CH:19]=[CH:20][N:21]=4)[CH2:13][CH:12]2[CH2:11][S:10][C:9]([NH2:22])=[N:8]3)=[CH:4][CH:3]=1
Reactant: O=C(NC1=NC2(c3ccc(F)s3)CN(c3ncccn3)CC2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC1=NC2(c3ccc(F)s3)CN(c3ncccn3)CC2CS1
Temperature: 58 °C
Yield: 85.1 %

Procedure:
To a stirred solution of the N-[7a-(5-fluoro-2-thienyl)-6-pyrimidin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (100 mg, 0.228 mmol) in ethanol (4.6 mL) is added pyridine (0.184 mL, 2.28 mmol) and O-methylhydroxylamine hydrochloride (190 mg, 2.28 mmol). The resulting mixture is heated at 58° C. for 15 hours. The solution is allowed to cool to room temperature, diluted with ethyl acetate (25 mL), and washed with dilute sodium bicarbonate ((20 mL) prepared from water (10 mL) and saturated sodium bicarbonate (10 mL)). The aqueous phase is extracted with ethyl acetate (25 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated. The residue is purified by silica gel flash chromatography eluting with dichloromethane/7 M ammonia in methanol, gradient from 99:1 to 95:5, to give the title compound (65 mg, 0.194 mmol, 85%) as a white solid. ES/MS (m/e): 336 (M+H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.C(C(CCCC(O)COC1C=CC(F)=CC=1)CC#CCCCC(O)=O)(=O)C>>[C:22]([O:21][CH:11]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)/[CH:10]=[CH:9]/[CH2:8][OH:7])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Agent: CC(=O)C(CC#CCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Product: CC(=O)OC(/C=C/CO)COc1ccc(F)cc1

Procedure:
The synthesis of this compound is carried out by the procedure of Example 4, Step B-5 except that an equivalent quantity of 1-(2-tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)-trans-2-pentene is substituted for the 1-(2-tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)-pentane of Example 4, Step B-5. The product is obtained as a viscous oil.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[CH:5]=[C:6]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)#[N:2].P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:4]1[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[N:7]=[C:6]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(-c2cc(=O)c(C#N)c(-c3ccc(Oc4ccccc4)cc3)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2cc(Cl)c(C#N)c(-c3ccc(Oc4ccccc4)cc3)n2)cc1
Temperature: 90 °C
Yield: 89 %

Procedure:
A mixture of methyl 4-(5-cyano-4-oxo-6-(4-phenoxyphenyl)-1,4-dihydropyridin-2-yl)benzoate (598.2 mg, 1.416 mmol) and phosphoryl trichloride (12 mL) was heated to 90° C. for 1 h then concentrated. The residue was dissolved in dichloromethane, washed with water and concentrated. Silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes, gave methyl 4-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)benzoate as white solid (0.5582 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (4H, s), 8.01-8.06 (2H, m), 7.89 (1H, s), 7.38-7.44 (2H, m), 7.20 (1H, t, J=7.40 Hz), 7.10-7.17 (4H, m), 3.97 (3H, s), MS (ES+) m/z: 441 (M+H); LC retention time: 4.333 min (analytical HPLC Method A).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].I[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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>[C:1]([NH:8][CH2:9][C:10]#[C:11][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of N-Boc propargylamine (2.07 g, 13.4 mmol), methyl 4-iodobenzoate (3.50 g, 13.4 mmol) and PdCl2(PPh3)2 (0.938 g, 1.34 mmol) in DMF (20 ml) was added triethylamine (9.31 ml, 126 mmol). The reaction mixture was stirred for 30 min at room temperature. Cu(I)I (0.508 g, 2.67 mmol) was added and stirring was continued for additional 16 h. The reaction mixture was diluted with ethyl acetate (250 ml), washed with 0.5M aqueous HCl (200 ml), and finally with brine (200 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/hexane (1/4) provided methyl 4-(N-Boc-3-aminoprop-1-ynyl)benzoate (3.44 g) as highly viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([Si](C)(C)C)=[CH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]2[O:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)c1cc2ncc(Br)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1cnc2ccoc2c1

Procedure:
6-Substituted-furo[3,2-b]pyridines of general formula (42), wherein Z is as defined in formula I, can be prepared as described in Scheme 8. 5-Bromo-3-hydroxypyridine can be treated with iodine and a base such as sodium carbonate to provide 5-bromo-3-hydroxy-2-iodopyridine. 5-Bromo-3-hydroxy-2-iodopyridine can be treated with. ethynyl(trimethyl)silane, a palladium catalyst and copper(I) iodide to provide 6-bromo-2-(trimethylsilyl)furo[3,2-b]pyridine. 6-Bromo-2-(trimethylsilyl)furo[3,2-b]pyridine can be treated with a base such as potassium carbonate to provide 6-bromo-furo[3,2-b]pyridine. 6-Bromo-furo[3,2-b]pyridine can be processed as described in previous Schemes, in particular Scheme 4, to provide 6-substituted-furo[3,2-b]pyridines of general formula (42).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[C@@H:15]([O:25][CH2:26][CH3:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[O:37][C:38]([CH3:44])=[C:39]([CH2:41][CH2:42]O)[N:40]=2)=[CH:32][CH:31]=1.O=C(CC)CC(OC)=O.ClC1C=CC(C(N)=O)=CC=1.CC1OC(C2C=CC=CC=2)=NC=1CCO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[C@@H:15]([O:25][CH2:26][CH3:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:42][CH2:41][C:39]2[N:40]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=3)[O:37][C:38]=2[CH3:44])=[CH:19][C:18]=1[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CCO
Agent: CCC(=O)CC(=O)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cc1oc(-c2ccccc2)nc1CCO
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2nc(-c3ccc(Cl)cc3)oc2C)cc1C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
To a ice cold solution of (S)-4-benzyl-3-[(2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionyl]-oxazolidin-2-one (100 mg, 260 μmol), 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (93 mg, 390 μmol) (prepared from methyl 3-oxopentanoate and 4-chloro-benzamide in analogy to the sequence described for the synthesis of 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol in M. Scalone, PCT WO 01/79202 A1) and triphenylphosphine (103 mg, 390 μmol) in tetrahydrofuran (2.5 ml) was added diethyl azodicarboxylate (61 μl, 390 μmol). The cooling bath was removed and stirring was continued for 12 h. Evaporation of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 70 mg (120 μmol, 45%) of the title compound as colorless oil.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH3:14])=[C:7]([NH:15][CH:16]([CH3:20])[CH:17]([CH3:19])[CH3:18])[N:6]2[N:21]=[CH:22][C:23]([C:24](Cl)=[O:25])=[C:5]2[N:4]=1.C(OCC)(=O)C>O1CCCC1>[Cl:2][C:3]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH3:14])=[C:7]([NH:15][CH:16]([CH3:20])[CH:17]([CH3:19])[CH3:18])[N:6]2[N:21]=[CH:22][C:23]([C:24]([NH2:1])=[O:25])=[C:5]2[N:4]=1
Reactant: N
Reactant: Cc1ccsc1-c1c(Cl)nc2c(C(=O)Cl)cnn2c1NC(C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccsc1-c1c(Cl)nc2c(C(N)=O)cnn2c1NC(C)C(C)C
Temperature: 22 °C
Reaction time: 16 h

Procedure:
At room temperature, 15 ml of concentrated aqueous ammonia were added to 4.0 g (10 mmol) of 5-chloro-7-(1,2-dimethylpropylamino)-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]pyrimidine-3-carbonyl chloride in 30 ml of tetrahydrofuran. The mixture was stirred at 22° C. for 16 hours, and 50 ml of ethyl acetate were then added. The organic phase was separated off, dried over sodium sulphate and concentrated under reduced pressure. This gave 3.0 g of 5-chloro-7-(1,2-dimethyl-propylamino)-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide (logPs=3.5; content according to HPLC: 94%)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][C:27]4[CH:28]=[CH:29][N:30]=[C:25]([Cl:24])[N:26]=4)=[CH:20][C:15]=3[O:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(O)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 294 mg (0.91 mMol) 6-hydroxy-benzo[d]isoxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide (Step 1.3), 149 mg (1.00 mMol) 2,4-dichlorpyrimidine and 426 mg (2.0 mMol) K3PO4 in 5 ml NMP is stirred for 20 h at rt. The reaction mixture is diluted with CH2Cl2 and 5% citric acid in water, the aq. phase separated off and extracted with CH2Cl2. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2→CH2Cl2/EtOAc 99:1) gives the title compound: MS: [M+1]+=435; TLC(CH2Cl2/EtOAc 49:1): Rf=0.66.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C:15]1[C:16](=[O:26])[N:17]([CH2:22][C:23](O)=[O:24])[C:18]([CH3:21])=[CH:19][N:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][NH2:38])[CH:35]=2)[NH:30][CH:29]=1.C([O-])=O.[NH4+]>[Pd].ClCCl>[CH3:21][C:18]1[N:17]([CH2:22][C:23]([NH:38][CH2:37][C:34]2[CH:35]=[C:36]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[C:28]3[CH3:27])=[O:24])[C:16](=[O:26])[C:15]([NH:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:20][CH:19]=1
Reactant: Cc1cnc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)c(=O)n1CC(=O)O
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NC[C@H]4CCCN4C(=O)OC(C)(C)C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
The title compound was prepared by a similar method to preparation 45 from 2-[3-({[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid [see preparation 54] and (3-methyl-1H-indol-5-yl)methylamine (72 mg, 0.45 mmol) [see preparation 36]. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0) changing to (95:5) in 1% increments 1H-NMR indicated starting chloro compound material. A mixture of this product with 10% palladium on charcoal (39.6 mg) and ammonium formate (439.5 mg,6.98 mmol) in dichloromethane (50 ml), was then stirred at room temperature overnight. Additional, 10% Palladium on charcoal (49 mg) was added and the mixture was heated under reflux for 48 hrs, after which time the catalyst was filtered off and the solvent evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and dried over MgSO4 and the solvent evaporated under reduced pressure to afford the title compound as a off-white solid, (44%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[NH2:15][C:16](N)=[O:17]>>[CH3:13][O:12][C:11]1[C:10]([CH3:14])=[CH:9][CH:8]=[C:3]2[C:2]=1[N:1]=[C:16]([OH:17])[N:15]=[C:4]2[OH:6]
Reactant: COC(=O)c1ccc(C)c(OC)c1N
Reactant: NC(N)=O
Product: COc1c(C)ccc2c(O)nc(O)nc12
Temperature: 155 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
A mixture of methyl 2-amino-3-methoxy-4-methylbenzoate (139.3 g, 0.714 mol) and urea (214.3 g, 3.57 mol) was heated in an oil bath at 110˜120° C. for 30 minutes. The temperature was then raised to 150-160° C. and the reaction mixture was stirred at this temperature for 8 h. TLC (petroleum ether/ethyl acetate=3:1) indicated the reaction was complete. The mixture was washed with EtOH (1.5 L) and water (1 L×6) and dried in vacuo to give the title compound (123 g, 83.7%) as a light brown solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O)[CH3:2].C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:26]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[S:3][CH2:1][CH3:2])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCSc1ccccc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCSc1ccccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(ethylthio)benzyl alcohol (3.98 g, 23.6 mmol) in THF (48 mL) at 0° C. under Ar was added DPPA (6.1 mL, 28.4 mmol) followed by DBU (4.0 mL, 26.0 mmol). The reaction was allowed to warm to room temperature and stirred for 2 days. The solution was concentrated to an oil, which was taken up in EtOAc, and washed successively with 10% aqueous citric acid, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated to an oil which was purified by silica gel chromatography (gradient elution with 100% hexanes to 5% EtOAc-hexanes). Concentration of the product fractions at reduced pressure afforded a pale yellow oil which was dried on a high vacuum line overnight to afford the title compound:
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:21]([O:25][C:26](=[O:33])[C:27]([C:30](Cl)=[O:31])=[N+:28]=[N-:29])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[CH3:9][O:8][C:6]([C@@H:5]1[CH2:4][CH2:3][C:2](=[O:10])[N:1]1[C:30](=[O:31])[C:27]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:33])=[N+:28]=[N-:29])=[O:7]
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1C(=O)C(=[N+]=[N-])C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 50.6 %

Procedure:
In a flask methyl(s)-(+)-2 pyrrolidone-5-carboxylate (1.0 g, 6.99 mmol) was dissolved in 40 mL THF and cooled to −78° C. LHMDS (8.0 mL, 8.0 mmol) 1.0M in THF was added and the reaction stirred at −78° C. for 25 mins. The chlorocarbonyl-diazo-acetic acid tert-butyl ester (1.7 g, 8.39 mmol, J. Org. Chem. 1994, 59, 1418) was then slowly added and the reaction stirred at −78° C. for 1.5 h, quenched at −78° C. with 5% citric acid and let warm to room temperature. Diluted with EtOAc, seperated, extracted 2× with EtOAc, washed with brine, and dried with magnesium sulfate. Concentrated under vacuum and purified by flash chromatography (10–30% EtOAc/hexanes) to give the product as a viscous yellow oil (1.1 g, 65%). 1HNMR (300 MHz, CDCl3) δ 1.51 (s, 9H) 2.1(m, 1H) 2.2–2.8 (m, 3H) 3.79 (s, 3H) 4.74 (dd, 1H, J 4.0 8.8).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:42])[C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:42])[C:37]([CH3:40])([CH3:41])[CH2:38][OH:39])=[CH:26][CH:25]=1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(CO)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ncnc23)c1F
Yield: 2.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 200 mg, 0.655 mmol), 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropanamido)methyl)benzoic acid (Intermediate-59, 237 mg, 0.78 mmol), oxalyl chloride (166 mg, 1.32 mmol), DMF (1 drop) and DIPEA (253 mg, 1.96 mmol) in CH2Cl2 (3 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.88 (d, 1H), 8.77 (s, 1H), 8.14 (m, 2H), 7.85 (m, 2H), 7.73 (s, 3H), 7.36 (m, 2H), 4.91 (t, 1H), 4.31 (d, 2H), 3.40 (m, 2H), 1.06 (s, 6H); MS [M+H]+: 591.29.