Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[N:21]=[C:20]([CH2:22][OH:23])[CH:19]=[CH:18][N:17]=1>O1CCCC1.C(OCC)(=O)C>[NH2:15][C:16]1[N:21]=[C:20]([CH2:22][O:23][S:11]([CH3:10])(=[O:13])=[O:12])[CH:19]=[CH:18][N:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nccc(CO)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 53 %

Procedure:
N,N-Diisopropylethylamine (490 μL, 2.9 mmol) and methanesulfonyl chloride (110 μL, 1.5 mmol) were added to a suspension of 2-amino-4-hydroxymethylpyrimidine (170 mg, 1.3 mmol, Reference Compound No. 4-1) in anhydrous tetrahydrofuran (5.0 mL) under ice-cooling, and the mixture was stirred for 7 hours at room temperature. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (300 mL), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the precipitated solid was filtered off with ethyl acetate, and dried under reduced pressure to give 140 mg of the title Reference Compound as a white solid (Yield: 53%).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2]1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][NH2:24].[C:25](#[N:28])[CH:26]=[CH2:27]>>[C:25]([CH2:26][CH2:27][N:24]([CH2:27][CH2:26][C:25]#[N:28])[CH2:23][CH2:22][N:21]([CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:13][NH2:12])#[N:28]
Reactant: NCCNCCNCCNCCN
Reactant: C=CC#N
Reactant: CCCCCCCCC1CO1
Product: CCCCCCCCC(O)CN(CCN)CCNCCN(CCN(CCC#N)CCC#N)CC(O)CCCCCCCC
Reaction time: 1 h

Procedure:
The oily reaction products from 2 moles of epoxy decane and 1 mole of tetraethylene pentamine (52.7 gms, 0.1 mole) is heated at 70°C as in the preceding example with 0.2 moles (10.6 gms) of acrylonitrile until refluxing ceases and for one hour additional. The product is a thick oil with cyano group present and decreased secondary amine shown by infrared examination.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[NH:22][C:21]([C:23]3[CH:28]=CC=CN=3)=[N:20][N:19]=2)=[CH:4][CH:3]=1.Cl[C:30]1C=CC(C2N=C3C=CC=CN3C=2CC(NN)=O)=CC=1.Cl.C(=N)(N)C(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[NH:22][C:21]([CH:23]([CH3:30])[CH3:28])=[N:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: NNC(=O)Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2nnc(-c3ccccn3)[nH]2)cc1
Agent: CC(C)C(=N)N
Agent: Cl
Product: CC(C)c1nnc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)[nH]1

Procedure:
The title compound was prepared according to the experimental described for compound 230 from 2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetohydrazide and isobutyrimidamide hydrochloride. M/e+ 352 for C19H19ClN5 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.05 (m, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.27 (m, 4H), 7.04 (t, J=7.3 Hz, 1H), 6.75 (t, J=6.6 Hz, 1H), 4.42 (s, 2H), 3.12 (m, 1H), 1.39 (s, 3H), 1.37 (s, 3H) ppm.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]([CH:31]([CH3:33])[CH3:32])[CH2:27][C:28](O)=[O:29].Cl.[CH3:35][O:36][C:37]([C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH2:43][C@H:42]2[NH2:48])=[O:38]>C1COCC1.C(OCC)(=O)C>[CH3:25][CH:26]([CH:31]([CH3:33])[CH3:32])[CH2:27][C:28]([NH:48][C@H:42]1[C:41]2[C:45](=[CH:46][CH:47]=[C:39]([C:37]([O:36][CH3:35])=[O:38])[CH:40]=2)[CH2:44][CH2:43]1)=[O:29]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: CC(C)C(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)CC(C)C(C)C)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
HATU (0.872 g, 2.3 mmol, 1 eq) and TEA (0.647 ml, 4.6 mmol, 2 eq) were added to an ice-cooled solution of 3,4-dimethylpentanoic acid (300 mg, 2.3 mmol, 1 eq) in THF (26 ml), and stirring was carried out for 15 min. (3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (0.786 g, 3.5 mmol, 1.5 eq) was added to the reaction solution, and the mixture was then stirred overnight at RT. The reaction solution was diluted with ethyl acetate, washed with sat. sodium hydrogen carbonate solution and sat. NaCl solution, dried over magnesium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, cyclohexane:ethyl acetate 2:1), the desired product was obtained. Yield: 87% (0.61 g)
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)([CH3:15])[CH3:14].[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[CH:31]([NH:33][C:34]1[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH2:44])[CH:40]=3)[N:35]=1)[CH2:30][CH2:29]2>>[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[CH:31]([NH:33][C:34]1[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH:44][C:1]([NH:22][CH:19]4[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]4)=[O:12])[CH:40]=3)[N:35]=1)[CH2:30][CH2:29]2
Reactant: CC(C)N1CCC(N)CC1
Reactant: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC(C)N1CCC(NC(=O)Nc2ccc3nc(NC4CCc5cccc(F)c54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-isopropyl-piperidin-4-ylamine (CAS no: 127285-08-9) and rac-N2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=462.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26](O)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][CH2:31][C:32](=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1>>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][C:32](=[O:41])[CH2:31][NH:30][C:26]([C:10]2[N:11]=[C:12]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:27])=[CH:39][CH:38]=1
Reactant: O=C(O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reactant: NCC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1)Cc1ccc(Cl)cc1

Procedure:
Adapted the procedure of example 2 using 3-benzyloxy-7-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid and 1-amino-3-(4-chloro-phenyl)-propan-2-one hydrochloride (AU2007001980) as starting material
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[OH:16][C:17]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(O)C>[CH2:23]([C:17]1([OH:16])[CH2:22][CH2:21][N:20]([CH:2]([CH3:15])[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)=[O:4])[CH2:19][CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(Cl)C(=O)c1ccc2c(c1)CC(=O)N2
Reactant: OC1(Cc2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C(=O)c1ccc2c(c1)CC(=O)N2)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
5-(2-Chloropropionyl)-2(1H,3H)-indolone (2.5 g, 11.2 mmol), 4-hydroxy-4-benzylpiperadine (2.1 g, 11.2 mmol), and triethylamine (1.56 ml, 11.2 mmol) were combined in ethanol and refluxed overnight. The mixture was cooled to room temperature and concentrated at reduced pressure. The residue was partitioned between ethyl acetate and water and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over calcium sulfate, and concentrated. The crude product was flash chromatographed on silica gel eluting first unreacted 5-(2-chloropropionyl)-2(1H,3H)-indolone with 1:1 ethyl acetate:hexane. Continued elution with ethyl acetate gave 3.6 g of product as a light brown foam. Recrystallization from ethyl acetate/hexane gave 1.23 g of purified title product. Less pure fractions from the column and mother liquors from the recrystallization were rechromatographed as above with 1:1 and then 3:1 ethyl acetate:hexane. Product fractions were triturated with ether/hexane to give 0.2 g more product for a total yield of 1.43 g, 34%; m.p. 188°-192° C.; NMR 8.22 (s, 1H), 8.08 (d, J=8 Hz, 2H), 7.99 (s, 1H), 7.31-7.13 (m, 5H), 6.89 (d, J=8 Hz, 1H), 4.03 (q, J=6.8 Hz, 1H), 3.57 (s, 2H), 2.72 (s, 2H), 2.72-2.58 (m, 3H), 2.46 (distorted t, 1H), 1.75-1.40 m, 4H), 1.26 (d, J=6.8 Hz, 3H), 1.23-1.19 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][N:24]([C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[Br:1][C:2]1[C:3]([N:34]2[CH2:35][CH2:36][C@@H:32]([N:24]([CH3:23])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:33]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (R)-tert-butyl methyl(pyrrolidin-3-yl)carbamate. LC-MS (Condition 6) tR=1.59 min, m/z=559.0/561.0 [M+H]+, m/z=502.9/504.9 [M+H—H2C═C(CH3)2].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[IH:22]>>[I:22][C:15]1[CH:20]=[C:19]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[N:18]=[CH:17][N:16]=1
Reactant: I
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccnc2ccccc12
Product: Ic1cc(-c2ccnc3ccccc23)ncn1

Procedure:
The compound was prepared according to Example 1 using quinoline-4-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: O.[CH2:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[CH3:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10]>>[OH:6][CH2:7][CH2:2][CH2:3][C:4]([OH:5])=[O:10].[CH3:12][N:11]1[C:9](=[O:10])[CH2:8][CH2:2][CH2:13]1
Reactant: O=C1CCCO1
Reactant: CC(=O)N(C)C
Solvent: O
Product: CN1CCCC1=O
Product: O=C(O)CCCO
Yield: 60 %

Procedure:
JP-A-1 186 864 (Derwent Abstr. 89-259000/36) discloses the preparation of N-alkylated lactams by reaction of the corresponding lactones with secondary amines in the presence of water via the corresponding N,N-dialkyl-omega-hydroxycarboxamides as intermediates. According to Example 1 of this patent application, the reaction of γ-BL with aqueous DMA gives an NMP yield of 60% and additionally forms methylamides of γ-hydroxybutyric acid. In the single further example according to the application, too, an NMP yield of 60% is reported for the corresponding reaction of γ-BL with DMA.
Reaction SMILES: CN1[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.ClC(Cl)(Cl)C(O)=O.[OH-].[Na+].C(OCC)(=O)C.CO.[CH2:37]([N:39](CC)CC)C>C1COCC1.C(OCC)(=O)C>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH2:6][CH2:37][NH2:39])=[CH:12]1
Reactant: CN1Cc2ccccc2S1
Reactant: CCN(CC)CC
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCc1ccccc1Sc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
2-Methyl-2,3-dihydro-benzoisothiazole (VI) (Hoffmann, R. W.; Goldman, S. Chem. Ber. 111, 1978, 2716-2725) (75 mg, 0.50 mmol) was dissolved in THF (1 mL) and added to indole (V) (140 mg, 0.60 mmol) under Ar. Tricloroacetic acid (90 mg, 0.55 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. 2 mL 1N NaOH (aq) was added. Extraction with ethyl acetate (2×10 mL) and purification by flash chromatography on silica gel (eluent: ethyl acetate then ethyl acetate/methanol/triethylamine) gave 88 mg [2-(1H-Indol-3-ylsulfanyl)benzyl]methyl amine (67% yield).
Reaction SMILES: [CH3:1][C:2]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15])([CH3:5])[CH2:3][OH:4].[H-].[Na+].I[CH3:19]>CN(C)C=O>[CH3:19][O:4][CH2:3][C:2]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15])([CH3:1])[CH3:5]
Reactant: Cc1cc2ccccc2n1C(C)(C)CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)(C)n1c(C)cc2ccccc21
Temperature: 0 °C
Yield: 96.9 %

Procedure:
To a solution of 2-methyl-2-(2-methyl-1H-indol-1-yl)propan-1-ol (780 mg, 3.8 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added sodium hydride (919 mg, 38.3 mmol) at 0° C. The resultant reaction mixture was allowed to stirred at 0° C. for 1H. Iodomethane (5.4 g, 38.3 mmol) was added dropwise at 0° C., And then the resulting reaction mixture was allowed to stir for 3 hours at room temperature. The reaction mixture was quenched with water. The pH was adjusted to around 6 by progressively adding 2N hydro chloride below 0° C. extracted with acetic ester (50 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 10:1→5:1) to give 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole (800 mg, 96%) as a light yellow oil. LCMS (M+H+) m/z: calcd. 217.15. found 217.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(OCC)(=O)C.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:20]=[CH:21][C:22]([O:25][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:23][CH:24]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OS(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
(+,-) cis 7-methoxy-4-(4-hydroxy-phenyl)-3-phenyl-chroman (7.5 g, 22.6 mmol) was dissolved in pyridine (35 ml), and methanesulfonylchloride (3.85 ml, 49.6 mmol) was added dropwise in 5 min. The reaction mixture was refluxed for 30 min, cooled to room temperature, and ethyl acetate (100 ml) was added. The reaction mixture was acidified with 6N Hydrochloric acid (100 ml), and the separated aqueous phase extracted with ethyl acetate (25 ml). The combined organic extracts were washed with 1N hydrochloric acid (50 ml), water (2×50 ml), dried with magnesium sulphate and evaporated to give a slightly yellow solid, which was recrystallised from ethanol, and vacuum dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:40].[CH3:41][N:42]([CH3:47])[CH2:43][CH2:44][CH2:45][NH2:46]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:46][CH2:45][CH2:44][CH2:43][N:42]([CH3:47])[CH3:41])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:40]
Reactant: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(NCCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide (0.056 g, 0.1 mmol) was dissolved in THF (5 mL) and N,N-dimethyl-1,3-propanediamine (0.035 g, 0.3 mmol) was added. The reaction was carried out and worked up as in Example 148 to give the title compound as a white amorphous solid. mp 141-144° C. LC-MS m/z 586 (M+H)+, 1.52 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37].O>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:36][OH:37])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NO
Reactant: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Intermediate (18b) (7.2 g, 15.5 mmol) was dissolved in pyridine (30 mL). Hydroxylamine hydrochloride (4.0 g, 57.9 mmol) was added followed by water (20 mL) and the mixture was stirred at 40° C. for 2 hours. The reaction was quenched with water, extracted with 200 mL EtOAc, washed with 3×100 mL 1M phosphoric acid, 1×100 mL saturated sodium bicarbonate solution, and 2×100 mL saturated aqueous NaCl, then dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-80% EtOAc:hexanes) to yield intermediate (18c) as a white solid (7.4 g). Anal. HPLC retention time=4.9 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent A over 6 minutes. MS m/z: [M+H+] calcd for C27H30FN3O4, 480.23. found 480.4. 1H-NMR (DMSO-d6) 10.99 (1H, s), 8.21 (1H, s), 7.67 (1H, d), 7.54 (1H, m), 7.44 (1H, s), 7.34 (1H, m), 7.11 (2H, m), 6.81 (2H, m), 5.73 (1H, d), 5.36 (2H, s), 5.10 (1H, d), 1.66 (2H, m), 1.13 (9H, s), 0.85 (4H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]#[N:11])=[N:2]2)=[CH:15][CH:16]=1
Reactant: N#Cc1n[nH]c2ccccc12
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C#N)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.47 g of 1H-indazole-3-carbonitrile (45.2 mmol, 1 eq.) were dissolved in 65 ml of dry DMF. 10 g of 1-(bromomethyl)-4-methoxybenzene (49.7 mmol, 1.1 eq.) and 17.7 g of cesium carbonate (54.2 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. Then the reaction mixture was partitioned between water and tert-butyl methyl ether. The separated aqueous layer was extracted twice with tert-butyl methyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crystallization from methanol provided 9.25 g (35.1 mmol, 77.7%) of analytically pure target compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[C:12]([O:16]C)(=O)[CH:13]=[CH2:14].[K].[C:19]1(C)C=CC=C[CH:20]=1.[OH-].[K+]>CC1CCCO1.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:14][CH2:13][C:12](=[O:16])[CH2:20][CH2:19]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Cc1ccccc1
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
6-Bromo-2,3-dihydro-1H-inden-1-one (800 g, 3.79 mol) and methyl acrylate (787 mL, 8.72 mol) in 2-methyl-tetrahydrofuran (4 L) were stirred at 28° C. Potassium tent-pentoxide solution in toluene (1.7 M, 2.68 L, 4.55 mol) was added dropwise keeping the temperature between 30° C. and 43° C. The mixture was stirred for 0.5 h at 25° C. Water (4 L) was added and after 10 min were KOH (383 g, 6.82 mol) added. The mixture was heated to reflux and the organic solvent was distilled off during 4 h. The mixture was cooled to 10° C., and the formed precipitate was filtered off and dried in vacuo to give the title compound (837 g, 75% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.74-1.85 (m, 2 H), 1.94 (m, 2 H), 2.34 (m, 2 H), 2.52-2.60 (m, 2 H), 3.27 (s, 2 H), 7.60 (d, 1 H), 7.79-7.83 (m, 1 H), 7.89 (m, 1 H); MS (ES+) m/z 293 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[NH:28]1[CH2:32][CH2:31][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1.C(N(CC)CC)C>C(#N)C.CCOC(C)=O>[C:36]([O:35][C:34]([NH:33][C@@H:30]1[CH2:31][CH2:32][N:28]([C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)[CH2:29]1)=[O:40])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(N)nc3c2CCCc2ccccc2-3)C1
Temperature: 25 °C

Procedure:
A solution of the product from Example 4C (1.5 g, 3.93 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (CAS #: 122536-77-0) (1.1 g, 5.9 mmol) and triethylamine (0.9 mL, 5.9 mmol) in acetonitrile (35 mL) was heated to 80° C. for 16 hours. The mixture was cooled to room temperature, diluted with EtOAc, washed with H2O and brine, dried (MgSO4), concentrated and chromatographed on silica gel eluting with ethyl acetate to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[Mg].[C:10]1(=[O:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>C(OCC)C>[Br:8][C:4]1[CH:3]=[C:2]([C:10]2([OH:20])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccccc21
Reactant: Brc1cccc(Br)c1
Agent: [Mg]
Solvent: CCOCC
Product: OC1(c2cccc(Br)c2)CCCc2ccccc21

Procedure:
To a solution of 1 g (4.2 mmol) 1,3-dibromobenzene in 10 mL diethyl ether was added 0.096 g (4 mmol) magnesium metal turnings. This mixture was stirred until all of the magnesium was consumed, at which time 0.29 g (2 mmol) 1-tetralone was added dropwise in 2 mL diethyl ether. The reaction was then heated to reflux for 30 min, after which the cooled reaction was quenched with a 10% HCl solution and extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate, filtered, and the solvent removed in vacuo to afford the crude product which was used without further purification.