Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:11]([CH2:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(NCc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)cccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(CCC(=O)OCc4ccccc4)cc3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from example 98A and benzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[S:24]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])(=[O:26])[NH2:25]>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:31]5[CH:32]=[CH:33][C:28]([S:24]([NH2:25])(=[O:27])=[O:26])=[CH:29][CH:30]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc(S(N)(=O)=O)cc3)cc1-2
Yield: 19 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 4-sulfamoylphenylboronic acid were reacted to give 192 (0.034 g, 19%). 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=2.3, 1H), 8.02 (d, J=8.4, 2H), 7.94 (s, 1H), 7.75 (t, J=12.6, 2H), 7.51 (dt, J=13.0, 6.5, 1H), 7.19 (d, J=8.4, 1H), 5.86 (dt, J=13.3, 6.7, 1H), 4.82 (s, 2H), 4.47 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 1.65 (d, J=6.6, 6H). MS (ESI(+)): m/z 468.1 (M+H)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:25][CH3:26])=[CH:22][CH:21]=[CH:20][CH:19]=2>CN(C)P(N(C)C)(N(C)C)=O.C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:26][NH:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH:14][C:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: CNc1c(N)cnc2ccccc12
Reactant: Cc1cc(C(=O)O)on1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CNc1c(NC(=O)c2cc(C)no2)cnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 245 mg of 3-methylisoxazole-5-carboxylic acid in 20 ml of hexamethylphosphoramide and 0.4 ml of acetonitrile is added 226 mg of thionyl chloride at -5°-0° C. After stirring at the same temperature for 30 minutes, 330 mg of 3-amino-4-methylaminoquinoline A15 is added and stirred at 0°-5° C. for 5 hours. The mixture is diluted with 50 ml of ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting solid is filtered and washed with water to give 361 mg (67%) of 4-methylamino-3-[(3-methylisoxazole-5-ylcarbonyl)amino]quinoline. It is suspended in 4 ml of hexamethylphosphoramide and 1 ml of acetic acid and stirred at 180° C. (bath temperature) for 40 minutes. The cooled mixture is poured into ice-water and neutralized with aqueous sodium bicarbonate. The resulting solid is filtered, washed with water and chromatographed on silica gel with dichloromethane-methanol (25:1 v/v) as eluent. The product obtained is recrystallized from dichloromethane-methanol to give 294 mg of C102 as white crystals melting at 281°-284° C. (dec.).
Reaction SMILES: CC1(C)C(=O)CCC1NC1C2N(C=CC=2)N=CC=1C(N)=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:30]([NH:31][CH:32]3[CH2:36][CH2:35][CH:34]([OH:37])[C:33]3([CH3:39])[CH3:38])=[C:29]([C:40]([NH2:42])=[O:41])[CH:28]=[N:27][N:26]2[CH:43]=1>>[Br:22][C:23]1[CH:24]=[C:25]2[C:30]([NH:31][CH:32]3[CH2:36][CH2:35][C:34](=[O:37])[C:33]3([CH3:39])[CH3:38])=[C:29]([C:40]([NH2:42])=[O:41])[CH:28]=[N:27][N:26]2[CH:43]=1
Reactant: CC1(C)C(O)CCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CC1(C)C(=O)CCC1Nc1c(C(N)=O)cnn2cccc12
Product: CC1(C)C(=O)CCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Yield: 81.4 %

Procedure:
Following conditions described in Step 1 of Intermediate 22, 6-bromo-4-(3-hydroxy-2,2-dimethylcyclopentylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (395 mg, 1.076 mmol, from Step 1) was converted to 6-bromo-4-(2,2-dimethyl-3-oxocyclopentylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (320 mg, 80% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (1 H, s), 7.69 (1 H, d, J=1.76 Hz), 7.16 (1 H, d, J=1.76 Hz), 2.36-2.73 (3 H, m), 1.89-2.06 (1 H, m), 1.15 (6 H, s); MS (ES+) m/z: 365.2, 367.1 (M+H).
Reaction SMILES: C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.C(OC([NH:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([NH:48][C:49]([NH:51][CH2:52][CH2:53][CH3:54])=[O:50])[CH:43]=2)(=[O:41])=[O:40])[CH:33]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=O)C=C.C(=O)(O)[O-].[Na+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([NH:48][C:49]([NH:51][CH2:52][CH2:53][CH3:54])=[O:50])[CH:43]=2)(=[O:41])=[O:40])[CH:33]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(NS(=O)(=O)c2cccc(NC(=O)NCCC)c2)c1
Agent: Cl[Pd]Cl
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCNC(=O)Nc1cccc(S(=O)(=O)Nc2cccc(C(N)CC(=O)OCC)c2)c1
Yield: 28.5 %

Procedure:
2.57 ml of acetic acid, 5.32 ml of tributyltin hydride and 177 mg of bis(triphenyl phosphine) palladium(II) chloride were added to a solution of 9.58 g of ethyl 3-{[(allyloxy)-carbonyl]-amino}-3-{{3-{[(3-{[(propylamino)-carbonyl]-amino}-phenyl)-sulphonyl]-amino}-phenyl}}-propanoate from Example II.2.g in 245 ml of dichloromethane, and the resultant mixture was stirred at room temperature for 22 h. An aqueous solution of sodium bicarbonate was added, and the mixture was extracted with dichloromethane. After drying the organic phase over magnesium sulphate, the solvent was removed, and the crude product was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give 2.30 g of the desired compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)[C:5](O)=[O:6].B.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH:4]([CH:5]=[O:6])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(CC(CCBr)C(=O)O)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: B
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C=O)CCBr)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
At 0° C., 10.7 g (33.95 mmol) of 4-bromo-2-[4-(methoxycarbonyl)benzyl]butanoic acid from Ex. VII in 200 ml of THF are treated with 40.74 ml (40.74 mmol) of a 1M solution of borane in THF, and the mixture is stirred with warming to room temperature for 2 hours. Excess borane is destroyed by addition of water. The mixture is extracted with ether and the organic phase is then dried over magnesium sulfate and the solvent is distilled off under reduced pressure. 10.23 g (33.92 mmol) of the highly unstable methyl 4-[4-bromo-2-(hydroxymethyl)butyl]benzoate remain, and this residue is immediately dissolved in 100 ml of methylene chloride and added dropwise to a suspension of 10.98 g (50.92 mmol) of pyridinium chlorochromate in 200 ml of methylene chloride. After 3.5 hours, the solution is filtered through silica gel which is washed thoroughly with ether, and the solvent is distilled off. The crude product is purified by flash chromatography on silica gel (0.04-0.063 nm) using methylene chloride/methanol 3/1 as mobile phase.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:20][CH:19]=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:27][CH:28]=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1

Procedure:
(E)-4-[1,3 Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid (from step (d) example 1, 560 mg, 1.13 mmol) was shaken with 10% palladium on carbon (500 mg) in DMF (100 mL) under hydrogen (30 psi) in a Parr apparatus for 6 h. Catalyst was filtered off (Celite) and volatiles evaporated in vacuo. The residual oil was solidified from DMF, filtered, dissolved in 1N sodium hydroxide, and then reprecipitated by addition of excess 1N hydrochloric acid. Such a sample was filtered, washed with water and dried to give title compound as a white powder, m.p. >300° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[Cl:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@]1(c2cc(N)ccc2Cl)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2Cl)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-chloro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-3) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white solid. MS (ISP): m/z=415.2 [M+H]+, 417.1 [M+2+H]+.
Reaction SMILES: [OH:1][N:2]1[C:6]([Br:7])=[C:5]([Br:8])[C:4]([Br:9])=[N:3]1.[N:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Br:9][C:4]1[C:5]([Br:8])=[C:6]([Br:7])[N:2]([O:1][C:16]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:17])[N:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: On1nc(Br)c(Br)c1Br
Product: O=C(On1nc(Br)c(Br)c1Br)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-3,4,5-tribromopyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (90%, crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[N:19]=[C:18]([Cl:20])[CH:17]=[C:16](Cl)[N:15]=2)=[CH:9][CH:8]=1)=[O:5].[S:26]1[C:30]([NH2:31])=[N:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[S:26]1[C:30]([NH:31][C:16]2[CH:17]=[C:18]([Cl:20])[N:19]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=4[Cl:1])=[CH:8][CH:9]=3)[N:15]=2)=[N:29][CH:28]=[N:27]1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)c1ccccc1Cl
Reactant: Nc1ncns1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ncns3)n2)cc1)c1ccccc1Cl
Temperature: 130 °C
Yield: 109.5 %

Procedure:
2-Chloro-N-(4-(4,6-dichloropyrimidin-2-ylthio)phenyl)benzamide (300 mg, 0.73 mmol), 1,2,4-thiadiazole-5-amine (74 mg, 0.73 mmol), Pd2 dba3 (36 mg), xantphos (46 mg), sodium carbonate (128 mg, 1.21 mmol) in 1,4-dioxane (10 mL) were flushed for 15 minutes with nitrogen and then heated in the microwave to 130° C. for 2 hours. The crude reaction mixture was poured in methanol, filtered through Celite and concentrated. Ethyl acetate and saturated aqueous sodium bicarbonate were added and the organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to yield 380 mg N-(4-(4-(1,2,4-thiadiazol-5-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)-2-chlorobenzamide with 50-60% purity (HPLC method A, Rf=8.576 minutes) that was used as such in the next step.
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH:24]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C@H:25]([C:36](O)=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.[CH3:49][O:50][C:51]([C@@H:53]([NH2:56])[CH2:54][OH:55])=[O:52].Cl.C1C=CC2N(O)N=NC=2C=1>O1CCCC1>[NH:24]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[C@H:25]([C:36]([NH:56][C@H:53]([C:51]([O:50][CH3:49])=[O:52])[CH2:54][OH:55])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.4 ml of N-ethylmorpholine and at 0° C, a solution of 10.5 g of DCC in 50 ml of tetrahydrofurane were added to a solution of 16.9 g (50 mmols) of Z-Trp-OH, 7.7 g (50 mmols) of H-Ser-OMe . HCl and 6.65 g (50 mmols) of HOBt in 100 ml of absolute tetrahydrofurane. The mixture was stirred for one hour at 0° C and for 2 hours at room temperature, the deposit was suction-filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and successively extracted with saturated NaHCO3 -solution, KHSO4 -solution, saturated NaHCO3 -solution and water. The ethyl acetate phase was dried over Na2SO4 and concentrated. The remaining oil was dissolved in 120 ml of isopropanol. When standing in the refrigerator the substance was crystallized. Yield: 15.6 g (71%), melting point: 143° - 145° C. [α]D25 = -16.8° (c=1, dimethylacetamide)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][C:20]1[CH:24]=[N:23][NH:22][C:21]=1[C:25](O)=[O:26]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:21]3[NH:22][N:23]=[CH:24][C:20]=3[CH3:19])=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: Cc1cn[nH]c1C(=O)O
Product: Cc1cn[nH]c1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)c1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-methyl-2H-pyrazole-3-carboxylic acid (CAS82231-51-4; B. Pelcman et al., WO2006032851) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=368.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[F:13][C:12]([F:15])([F:14])[C:11]1[N:6]2[CH:5]=[N:4][C:3]([C:1]#[C:2][C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ncc(Br)cn1
Product: Nc1ncc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.18) (178 mg, 0.5 mmol) and commercially available 2-amino-5-bromo-pyrimidine (87 mg, 0.5 mmol) according to general procedure II. Obtained as a dark red solid (92 mg, 41%). MS (EI) 447.1 [(M+)]; mp 294° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH2:9].C(N(CC)CC)C.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(Br)c(N)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(Br)c(NC(=O)C2CC2)c1

Procedure:
The solution of 13.95 g of 2-bromo-5-methylphenylamine in 250 ml of chloroform is cooled to 0° C. with stirring and admixed with 12.6 ml of triethylamine. 7.56 ml of cyclopropanecarbonyl chloride are slowly added dropwise. The mixture is stirred for 1 hour each at 0° C. and at room temperature. The reaction mixture is poured onto water (400 ml) and extracted with dichloromethane (1×250 ml). The organic phases are washed with brine (350 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of crystallization from ethyl acetate. Rf=0.37 (1:4 EtOAc-heptane); Rt=4.19.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+].[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CC(O)=O.O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][CH2:2][O:16][C:13](=[O:15])[CH3:14])=[CH:7][CH:8]=1
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCC(=O)c1ccc(F)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
To a solution of 3-chloro-1-(4-fluorophenyl)-propan-1-one (4.0 g, 21.5 mmol) in AcOH (30 ml) in a sealed tube are added sodium acetate (8.64 g, 105.4 mmol) and potassium iodide (0.36 g, 2.15 mmol) at RT. The reaction mixture is stirred at 130° C. for 16 h. After completion of reaction, the mixture is diluted with water (60 ml) and neutralized with aqueous sodium carbonate at 0° C. The aqueous layer is extracted with DCM (3×100 ml). The combined organic layers are washed with water (200 ml), brine (200 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to get the crude product, which is purified by column chromatography (silica gel, 10% EtOAc/hexane) to yield acetic acid [3-(4-fluorophenyl)-3-oxo-propyl]ester (3.00 g, 14.3 mmol, 66%).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH2:6][NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][O:17][C:18](=[O:20])[N:19]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+]>O1CCOCC1.O>[O:17]1[C:18](=[O:20])[N:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:22])=[O:3])=[O:21])=[CH:10][CH:11]=2)[NH:16]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 3 (0.60 g, 2.0 mmol) was dissolved in a mixture of 1,4-dioxane/H2O (10 mL, 1/1, v/v). Aq. NaOH (2.0 mL, 2N) was added and the mixture was stirred for 3 h at RT. The reaction mixture was neutralized with Dowex H+ and filtered. The filtrate was concentrated under reduced pressure and the resulting white solid was dried under vacuum. Yield 0.51 g (93%).
Reaction SMILES: N#N.[Br:3][C:4]([F:11])([F:10])[C:5]([O:7]CC)=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:3][C:4]([F:10])([F:11])[C:5]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C1CCNC1
Agent: N#N
Product: O=C(N1CCCC1)C(F)(F)Br
Temperature: 50 °C
Reaction time: 18 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), ethyl bromodifluoroacetate (0.88 mL, 6.89 mmol) was added dropwise to pyrrolidine (0.58 mL, 6.89 mmol) at rt. The reaction mixture was stirred at 50° C. for 2 h and at rt for 18 h. The mixture was then filtered through silica and the title compound obtained as a colorless oil. LC-MS-conditions 08: tR=0.70 min; [M+H]+=228.01.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:11]([C:24](OCC)=[O:25])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:3]=1.[BH4-].[Li+].O>C(O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH:11]([CH2:24][OH:25])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:3]=1
Reactant: CCOC(=O)C1c2c(oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc23)CCN1Cc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2CCc3oc4c(Cl)cc(S(=O)(=O)c5ccccc5)cc4c3C2CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
The product obtained from step A (269 mg, 0.50 mmol) was dissolved in ethanol (10 mL) at 0° C. Lithium borohydride (220 mg, 10.0 mmol) was added slowly and the reaction mixture was stirred at ambient temperature for 2 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over MgSO4, filtered, and the filtrate concentrated in vacuo. Purification by flash column chromatography (SiO2, 9:1 to 7:3 hexanes/ethyl acetate) afforded (6-chloro-2-(4-methoxybenzyl)-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-1-yl)methanol (149 mg, 60%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.05-7.94 (m, 3H), 7.86-7.83 (m, 1H), 7.57-7.48 (m, 3H), 7.26-7.21 (m, 3H), 6.92-6.87 (m, 2H), 4.02-3.98 (m, 1H), 3.82 (s, 3H), 3.83-3.80 (m, 1H), 3.72 (s, 2H), 3.64-3.57 (m, 1H), 3.29-3.19 (m, 1H), 3.12-2.98 (m, 2H), 2.68-2.60 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([NH2:21])=[O:20])=[CH:5]2.Br[C:23]1[CH:28]=[CH:27][N:26]2[CH:29]=[C:30]([CH2:32][O:33][CH3:34])[N:31]=[C:25]2[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu](I)I.O.O1CCOCC1>[CH3:34][O:33][CH2:32][C:30]1[N:31]=[C:25]2[CH:24]=[C:23]([NH:21][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])[CH:28]=[CH:27][N:26]2[CH:29]=1
Reactant: NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: COCc1cn2ccc(Br)cc2n1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COCc1cn2ccc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cc2n1
Temperature: 150 °C
Yield: 91.6 %

Procedure:
20 mg (0.09 mmol) of copper iodide, 40 mg (0.14 mmol) of 5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 1.2, 27 mg (0.11 mmol) of 7-bromo-2-methoxymethylimidazo[1,2-a]pyridine, prepared according to the protocol described in step 8.3, 50 mg (0.36 mmol) of potassium carbonate and 3 mL of anhydrous dioxane are placed in a 10 mL pressure tube specific for microwave reactors. The suspension is degassed for a few minutes, and 0.01 mL (0.04 mmol) of trans-1,2-cyclohexanediamine is then added. The tube is then sealed and heated in the microwave reactor at 150° C. for two 1-hour cycles. After this time, the suspension cooled to room temperature is poured into 20 mL of water and then extracted with 2×30 mL of dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 45 mg of the expected product are thus obtained.