Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH:22]([OH:28])[CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:28][CH:22]2[CH2:21][C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1
Yield: 65.5 %

Procedure:
In a manner similar to Example 12A, the reaction of 1.54 g (0.007 mole) of (+)-cis-3-(2,2-dichloroethenyl)-2,2-dimethyl-cyclopropanecarbonyl chloride and 1.5 g (0.007 mole) of (+)-4-phenyl-2-indanol (EE≥95%) in the presence of 0.7 g (0.009 mole) of pyridine and 20 ml of toluene gave 1.84 g of (+)-4-phenyl-2-indanyl (+)-cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate as an oil, EE≥95% (alcohol moiety). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:23]([Cl:22])=[O:25])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(Nc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(N(C(=O)Cl)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a cooled solution of 3-methoxy-N-phenylaniline (100.0 mg, 0.502 mmol) and pyridine (0.102 mL, 1.267 mmol) in DCM (500 mL) was added triphosgene (120.0 mg, 0.406 mmol). The solution was allowed to warm up to room temperature and stirred overnight. The organic solvent was evaporated. The residue was dissolved in ethyl acetate, washed with water, brine, dried over MgSO4 and concentrated to provide the title compound (105.0 mg). LCMS m/z=261.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.79 (s, 3H), 6.90-7.31 (m, 3H), 7.32-7.52 (m, 4H), 7.52-7.70 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[N:6]=2.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:13][O:12][C:7]1[N:6]=[C:5]2[N:4]([CH3:14])[C:3]([CH2:2][O:1][C:16]3[CH:48]=[CH:47][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:22]4=[O:46])=[CH:18][CH:17]=3)=[N:11][C:10]2=[CH:9][CH:8]=1
Reactant: COc1ccc2nc(CO)n(C)c2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.25 g of 2-hydroxymethyl-5-methoxy-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 69), 0.66 g of 5-(4-hydroxy-benzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.35 ml of tributylphosphine, 0.36 g of 1,1'-(azodicarbonyl) di-piperidine and 15 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.70 g of the title compound, melting at 80-85° C. (softening).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[C@H:13](O)[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([O:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:27]([O:30][N:31]([C@H:13]1[CH2:12][N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])[CH:15]=[C:14]1[CH:16]1[CH2:17][CH2:18]1)[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C(C2CC2)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-cyclopropyl-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 264, 3 g, 7.82 mmol) and N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9, 2.020 g, 7.82 mmol) following the procedure described for Intermediate 10. The desired product was obtained as a yellow oil (3.62 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([CH3:12])[CH:3]=1.[K+].[CH3:14][O:15][C:16](=[O:21])[CH2:17]C([O-])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH2:17][C:16]([O:15][CH3:14])=[O:21])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(F)ccc1CC(=O)O
Reactant: COC(=O)CC(=O)[O-]
Agent: [K+]
Product: COC(=O)CC(=O)Cc1ccc(F)cc1C
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield from 2-(4-fluoro-2-methylphenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 2.24 (3H, s), 3.47 (2H, s), 3.74 (3H, s), 3.83 (2H, s), 6.88-6.94 (2H, m), 7.07-7.12 (1H, m).
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:14][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccccc1C=O
Reactant: CC(C)(C)N
Solvent: Cc1ccccc1
Product: Cc1ccccc1C=NC(C)(C)C
Yield: 92.1 %

Procedure:
A stirred solution of o-tolualdehyde (25 g, 0.21 mol), and t-butylamine (27.75 g, 0.38 mol) in toluene (250 mL) was refluxed under standard Dean-Stark conditions for 20 h. The solution was evaporated to an oil which was vacuum distilled (bp 70°-73° C., 0.6 mm Hg) to afford 33.9 g (93%) of product: IR (neat) 2980, 1645, 1605, 1460, 1375, 1210, 960, 910 cm-1 ; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1 H), 7.86-7.83 (m, 1 H), 7.25-7.11 (m, 3 H), 2.46 (s, 3 H), 1.30 (s, 9 H); 13C NMR (CDCl3, 100 MHz) δ 153.7, 137.1, 135.1, 130.5, 129.6, 127.1, 126.4, 57.5, 29.8, 19.2; GC RT 7.6 min (DB-1, 30 m×0.53 mm, program: 100° C. for 5 min, 100°-260° C. at 15° C./min, hold at 260° C. for 12 min).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[O:12][C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>N1C=CC=CC=1>[Cl:21][C:16]1[CH:15]=[C:14]([NH:13][C:11]2[O:12][C:8]([CH2:7][O:6][C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:25](=[O:26])[O:27][CH:28]([CH3:30])[CH3:29])=[CH:3][CH:4]=3)=[N:9][N:10]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: Nc1ccc(OCc2nnc(Nc3ccc(Cl)c(Cl)c3)o2)cc1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(OCc2nnc(Nc3ccc(Cl)c(Cl)c3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To a stirred solution of 5-((4-aminophenoxy)methyl)-N-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-amine (130 mg, 0.370 mmol) in pyridine (1 mL) at 0° C., isopropyl chloroformate (1 M solution in toluene, 0.370 mL, 0.370 mmol) was added and the reaction was stirred at room temperature overnight. Solvent was removed under vacuum. The residue was filtered and purified by preparative HPLC to obtain isopropyl (4-((5-((3,4-dichlorophenyl)amino)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)carbamate (0.03 g, 14%). 1H NMR: 400 MHZ, DMSO-d6: δ 1.24 (d, J=6.00 Hz, 6H), 4.87 (t, J=6.40 Hz, 1H), 5.26 (s, 2H), 6.99 (dd, J=2.40, 6.80 Hz, 2H), 7.39 (d, J=8.80 Hz, 1H), 7.47 (dd, J=2.80, 9.00 Hz, 1H), 7.61 (d, J=8.80 Hz, 1H), 7.88 (d, J=2.80 Hz, 1H), 9.40 (s, 1H), 11.00 (s, 1H). LCMS: RT 2.11 min. LCMS (ES-API), m/z 439.0 (M+H).
Reaction SMILES: [CH2:1]([O:8]C1C=C2C(C(C=O)=CN2)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](Cl)[CH:30]=2)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[CH:24]=1)(=[O:22])[NH2:21]>>[CH2:1]([O:8][C:28]1[CH:27]=[C:26]2[C:31]([C:23]([C:20](=[O:22])[NH2:21])=[CH:24][N:25]2[CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: NC(=O)c1cn(CC(=O)O)c2ccc(Cl)cc12
Product: NC(=O)c1cn(CC(=O)O)c2cc(OCc3ccccc3)ccc12

Procedure:
was prepared from 6-benzyloxy-1H-indole-3-carbaldehyde [92855-64-6] using similar protocols as described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 325 [M+H]+, 649 [2M+H]+; tR (HPLC conditions b): 4.06 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1COCC1>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:28](=[O:30])[CH3:29])[CH:21]=[CH:20]3)[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCc2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)n1ccc2cc(Oc3cc(COCc4ccccc4)ncn3)ccc21

Procedure:
To a solution of 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1 H-indole (12 g, 36.2 mmol) in THF (300 mL), NaH (1.74 g, 43.5 mmol) and acetic anhydride (5.13 mL, 54.3 mmol) are added. After 1 h the reaction is quenched with aqueous ammonium chloride and extracted with EtOAc. Most of the impurities are removed passing it through a silica gel column eluting with 50:50 heptane:EtOAc to give crude 1-[5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indol-1-yl]-ethanone. This is then dissolved in TFA (300 mL) and heated to 100° C. for 6 hours. At this point the solvent is removed and 1-[5-(6-hydroxymethyl-pyrimidin-4-yloxy)-indol-1-yl]-ethanone isolated via FCC eluting with EtOAc. MS (ESI) m/z 284.0 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.[C:12]([Si](C)(C)C)#[CH:13]>CO>[C:12]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1)#[CH:13]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnnc2ccccc12
Solvent: CO
Product: C#Cc1cnnc2ccccc12

Procedure:
The title compound can be synthesized from 4-ethynylcinnoline and N-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1 (nitro reduction performed in a manner similar to that described for Example 10; 0.25M in MeOH/10% AcOH). 4-ethynylcinnoline is prepared from 4-bromocinnoline and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [Si]([Cl:5])(C)(C)C.[CH3:6][N:7]([CH3:37])[C:8]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:13][CH2:12][CH:11]([NH:14][C@@H:15]([CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH2:10][CH2:9]1>CC(CC)=O>[ClH:5].[ClH:5].[CH3:37][N:7]([CH3:6])[C:8]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:13][CH2:12][CH:11]([NH:14][C@@H:15]([CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[C:16]([N:18]([CH3:19])[CH3:20])=[O:17])[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C(=O)[C@H](Cc1c[nH]c2ccccc12)NC1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
Me3SiCl (0.3 ml, 2.4 mmol) was added to a solution of (S)-2-(4-(dimethylamino)-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-N,N-dimethylpropanamide (420 mg, 0.9 mmol, polar diastereomer from step 3) in ethyl methyl ketone (10 ml). The solid was aspirated after a reaction time of 1 h.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[CH:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CCN(CC)CC.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[C:28][C:38]([N:37]([CH3:41])[CH3:36])=[O:39])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(C(=O)NC(CC#CC(=O)N(C)C)C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound from Step A of Example 49 (0.389 g, 1 mmol) was dissolved in dry DMF (5 mL) with dichlorobis(diphenylphosphine)palladium (II) (0.02 eq), CuI (0.02 eq), Et3N (0.4 eq, 3 mL), and N,N-dimethylcarbamyl chloride (1.0 eq, 92 μL). The reaction mixture was stirred overnight at room temperature and then at 70° C. for 1 hour. The mixture was filtered through a pad of Celite and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc/hexanes, 2:3) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[N:18]1([CH2:24][CH2:25][C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[C:28]([C:35](Cl)=[O:36])[N:27]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:35]([C:28]2[N:27]=[C:26]([CH2:25][CH2:24][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=23)=[O:36])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a solution of 4-chlorobenzylamine (0.080 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (85 mg, 47%). 1H NMR (DMSO-d6) δ 8.52 (1H), 8.35 (1H), 8.05 (1H), 7.35 (4H), 7.08 (1H), 6.85 (1H), 4.45 (2H), 3.58 (4H), 3.20 (2H), 2.78 (2H), 2.45 (4H); m/z (M+H)=399.16.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[C:4](Cl)[N:3]=1.[CH3:10][NH:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH2:20])=[O:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:10][NH:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:20][C:4]1[C:5]([Cl:8])=[CH:6][N:7]=[C:2]([Cl:1])[N:3]=1)=[O:13]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC(=O)[C@@H]1CCCC[C@@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)[C@@H]1CCCC[C@@H]1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
2,5,6-trichloropyrimidine (368 mg, 2.0 mmol), cis-2-amino-cyclohexanecarboxylic acid methylamide (308 mg, 2.0 mmol), and N,N-diisopropylethylamine (387 mg, 3.0 mmol) were combined in 10 mL isopropyl alcohol and stirred at room temperature for 24 hours. The reaction was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated and was dried (sodium sulfate) to afford a solid which was purified on silica gel (1% to 3% methanol:dichloromethane gradient elution) to afford 502 mg (83%) of cis-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methylamide as a white foam. Mp: 108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[O:13][CH2:14][C:15](=[O:22])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][N:30]=2)[C:25]([CH:32]=O)=[CH:24]1.N1CCCCC1>C(O)C>[NH:23]1[C:31]2=[N:30][CH:29]=[CH:28][CH:27]=[C:26]2[C:25]([CH:32]=[C:14]2[O:13][C:12]([NH:11][C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[O:2][CH3:1])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]2=[O:22])=[CH:24]1
Reactant: CCOC(=O)C1=C(Nc2ccc(OC)cc2OC)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OC)cc2OC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 27.1 %

Procedure:
To a solution of ethyl 2-[(2,4-dimethoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.1 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.12 g, 1.1 mmol) in ethanol (10 mL), piperidine (0.5 mL, 4.6 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound (0.13 g, y. 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2([C:13]([O:15][CH2:16]C)=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]2[OH:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]2[O:12][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1(Cc2ccc(C)cc2)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1(Cc2ccc(C)cc2)CCCC1OC(=O)c1ccccc1

Procedure:
5.24 grams of 2-p-methylbenzyl-2-ethoxycarbonyl-cyclopentanol obtained in Example 18 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 2.44 ml of pyridine was slowly added, then 3.55 ml of benzoyl chloride was dropwise added. Upon the completion of the addition, the reaction was continued under reflux condition for 12 hours. Then the procedure as described in Example 23 was followed, to give 7.41 g of yellow liquid. MS: m/e 367(M++1), 366(M+), 293(M+—CO2CH2CH3), 261(M+—C6H5CO2), 216, 198, 170, 155, 105, 91, 77.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a suspension of crude 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (423 mg, 1.5 mmol) in N,N-dimethylformamide (3 mL) is added 4-(4-Methyl-piperazin-1-yl)-phenylamine (290 mg, 1.5 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to room temperature and addition of 2 mL of water, the product precipitated out. The precipitate is then filtered off, washed with water, and dried to yield 0.5 g of crude 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione, which is used as such for the next reaction.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:21][CH2:22][CH2:23][CH2:24]I>CCCCCCC.CCOC(C)=O>[Cl:21][CH2:22][CH2:23][CH2:24][N:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]=2[O:12][CH2:11][C:10]1=[O:14]
Reactant: CC(C)c1cccc2c1OCC(=O)N2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc2c1OCC(=O)N2CCCCl
Yield: 69.7 %

Procedure:
8-Isopropyl-4H-benzo[1,4]oxazin-3-one (95MF83) (0.115 g, 0.60 mmol), Cs2CO3 (0.293 g, 0.90 mmol) and 3-chloro-1-iodopropane (0.135 g, 0.66 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF98) (0.112 g, 70%). 1H NMR (CDCl3) δ 7.03-6.95 (m, 2H), 6.93-6.90 (m, 1H), 4.57 (s, 2H), 4.09 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.33-3.25 (m, 1H), 2.20-2.13 (m, 2H), 1.22 (d, J=7.2 Hz, 6H); 13CNMR (CDCl3) δ 164.9, 142.8, 137.8, 128.5, 122.8, 121.4, 112.5, 67.7, 42.5, 39.3, 30.3, 27.2, 22.7.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCOCC2)nc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
A mixture of methyl 6-chloronicotinate (1.02 g, 5.93 mmol), morpholine (0.57 ml, 6.52 mmol), potassium carbonate (1.06 g, 7.71 mmol) and DMF (20 ml) was stirred at 100° C. for 6 hrs. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and concentrated under reduced pressure. The obtained solid was collected by filtration and washed with diisopropy ether to give the title compound (0.93 g, 71%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:10]([F:11])=[CH:9][C:8](F)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2].C(N(CC)CC)C.[C:23]([O:27][C:28](=[O:35])[NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:10]([F:11])=[CH:9][C:8]([N:32]2[CH2:33][CH2:34][C@H:30]([NH:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:35])[CH2:31]2)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1c(F)cc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(F)cc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 69.8 %

Procedure:
A solution of 2,3,4,6-tetrafluorobenzoic acid ethyl ester (Example 1b, 5.1 g, 22.9 mmol), triethylamine (22 mL, 157 mmol), and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (5.2 g, 27.9 mmol) in acetonitrile (60 mL) is stirred at room temperature for 64 hours. The mixture is concentrated in vacuo and the residue dissolved in chloroform, washed with NaHCO3 and then brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford a solid. The solid is purified by column chromatography (1:1:7 ethyl acetate/chloroform/hexanes) to afford the title compound (6.21 g). 1H NMR (CDCl3): δ 6.07 (ddd, 1H), 4.78–4.63 (bd, 1H), 4.49–4.22 (m, 3H), 3.80–3.68 (m, 1H), 3.66–3.28 (m, 3H), 2.33–2.13 (m, 1H), 2.04–1.83 (m, 1H), 1.45 (s, 9H), 1.36 (t, 3H).