Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:66][C:67]1[CH:74]=[C:73]([O:75][CH3:76])[CH:72]=[CH:71][C:68]=1[CH:69]=[O:70].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:76][O:75][C:73]1[CH:72]=[CH:71][C:68]([CH:69]=[O:70])=[C:67]([O:66][CH2:23][C:22]2[CH:21]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH:25]=2)[CH:74]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(COc2cc(OC)ccc2C=O)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3,4,5-Tri(octadecyloxy)benzylchloride (93.6 g, wet, <90.8 mmol), 2-hydroxy-4-methoxybenzaldehyde (15.2 g, 0.10 mol) and potassium carbonate (31.4 g, 0.23 mol) were suspended in DMF (830 ml), and the suspension was stirred at 80° C. overnight. The reaction mixture was dissolved in chloroform (1600 ml), and the mixture was washed 3 times with 1N hydrochloric acid (800 ml), once with 5% aqueous sodium hydrogen carbonate solution (800 ml), and once with 20% brine (800 ml). The solvent was evaporated, and the residue was precipitated with methanol (800 ml) and washed with acetonitrile (800 ml) to give 4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzaldehyde (93.5 g, 89.2 mmol, 98%).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].[NH2:21][C@@H:22]([CH2:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=1)[C@H:23]([OH:35])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH3:34])[CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:43][C:41]1[CH:42]=[C:37]([CH:38]=[C:39]([F:44])[CH:40]=1)[CH2:36][C@H:22]([NH:21][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:1][CH2:2][CH3:3])[CH2:18][CH2:19][CH3:20])=[CH:10][CH:11]=1)=[O:17])[C@H:23]([OH:35])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH3:34])[CH:28]=1
Reactant: CCCN(CCC)c1nccc2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)c1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a stirred solution of 1-(dipropylamino)isoquinoline-7-carboxylic acid (103 mg, 0.38 mmol), (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (154 mg, 0.38 mmol), HOBt (77 mg, 0.57 mmol), and DIPEA (0.2 mL, 1.1 mmol) in methylene chloride (4 mL) was added HATU (216 mg, 0.57 mmol). The reaction mixture was stirred overnight and then partitioned between methylene chloride and 1 N hydrochloric acid. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9:1 chloroform/methanol) gave N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1-(dipropylamino)isoquinoline-7-carboxamide (70 mg): mp: 142–151° C.; APCI MS m/z 589 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[NH2:10][C:11]1[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1>C(O)=O.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:17]/[C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:10])[N:16]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1ccnc(N)n1
Reactant: O=Cc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: Nc1nccc(/C=C/c2cncc(Br)c2)n1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A solution of 5-bromo-pyridine-3-carbaldehyde (436 mg, 2.34 mmol) and 2-amino-4-methylpyrimidine (246 mg, 2.35 mmol) in formic acid (96%, 3 mL) was heated for 18 h. After cooling to rt, it was then diluted with water and basified to pH ˜13 with 1 N NaOH. The mixture was then extracted with methylene chloride. The combined extracts was washed with water (1×), dried over MgSO4 and concentrated. The residue was chromatographed on silica gel eluting with CH2Cl2:MeOH:NH4OH (100:5:0.5) to give the title compound (463 mg, 71%). MS (DCI/NH3) m/z 277, 279 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[SH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]2[CH:16]=[CH:17][C:2]([S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N:3][CH:4]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Reactant: O=C(O)CCS
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 60 °C
Yield: 66.3 %

Procedure:
To a solution of 6-chloro-N-(4-fluorophenyl)nicotinamide (0.20 g, 0.80 mmol) in 10 mL of DMF was added 3-mercaptopropionic acid (0.10 mL, 1.2 mmol) and potassium tert-butoxide (0.31 g, 2.8 mmol) and the mixture heated to 60° C. After 9 h the reaction mixture was poured into ice water, HCl (1 M, aq) added to adjust to pH 6, and the solids removed via filtration. The filtrate was then taken to pH 10 with NaOH (4M, aq) and extracted with ethyl acetate. HCl (6M, aq) was then added to the filtrate to adjust the pH to 4 and extracted with ethyl acetate, dried over sodium sulfate, and the solvents removed in vacuo to yield a white solid. Purification by recrystallization using ethyl acetate gave 0.17 g (66%) of the titled product as a white solid; MS (EI) m/z 319.20 (M−H)−.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:33])[N:9]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1)[CH:10]1[CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+]>O>[C:3]([O:7][C:8](=[O:33])[N:9]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1)[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 20 mL of a methanol solution containing 1.4 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate, 5 mL of water and 0.53 g of potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour and 15 minutes. The solvent was removed under reduced pressure, and ethyl acetate and water were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.0 g of a pale yellow oily substance, tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:28].C(O)(=O)C>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[Br:28])(=[O:10])[CH3:9]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.67 h

Procedure:
To β-D-glucose pentaacetate (5 g, 12.81 mmol) was added 33% HBr in acetic acid (30 mL, 192 mmol) at rt. After stirring for 40 min, the mixture was diluted with CH2Cl2 (150 mL) and washed with ice cold water until the washings were neutral pH. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 2.06 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 2.13 (s, 3H), 4.15 (d, J=11.1, 1H), 4.31-4.37 (m, 2H), 4.86 (dd, J=9.9, 4.0, 1H), 5.19 (t, J=9.8, 1H), 5.58 (t, J=9.8, 1H), 6.63 (d, J=4.0, 1H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH2:13])=[O:12])=[C:7]([O:16][CH2:17][C:18](=[O:20])[NH2:19])[CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].F[C:28]1[CH:29]=[C:30]([O:37][CH3:38])[CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35]>CC(N(C)C)=O.O>[C:18]([CH2:17][O:16][C:7]1[CH:6]=[C:5]([S:2]([NH:1][C:28]2[CH:29]=[C:30]([O:37][CH3:38])[CH:31]=[CH:32][C:33]=2[N+:34]([O-:36])=[O:35])(=[O:3])=[O:4])[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11]([NH2:13])=[O:12])(=[O:20])[NH2:19]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: NC(=O)COc1ccc(S(N)(=O)=O)cc1OCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(NS(=O)(=O)c2ccc(OCC(N)=O)c(OCC(N)=O)c2)c1

Procedure:
A mixture of 4-aminosulfonyl-2-carbamoylmethoxyphenoxyacetamide (Intermediate A66, 12.1 g, 0.040 mol), potassium carbonate (11.0 g, 0.80 mol), and dimethylacetamide (160 mL) was heated at reflux as 3-fluoro-4-nitroanisole (6.84 g, 0.040 mol) in 40 mL dimethylacetamide was added dropwise over 40 min. After an additional 30 min at reflux, the mixture was allowed to cool overnight. It was then diluted with 200 mL of water and filtered with the aid of additional water. The filtrate was brought to pH 5, and the resulting solid was collected and washed with water. After air-drying, the product, title compound weighed 15 g (80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.O.[NH2:22][NH2:23].N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH:22][NH2:23])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Cl)cc1
Agent: N
Solvent: O
Product: NNc1ccc(NC(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Dissolving 20 (6.5 g, 22 mmol) in hot alcohol (150 mL) and adding slowly a mixture of 100% hydrazine hydrate (1.6 mL), concentrated aqueous ammonia (1.7 mL) and alcohol (5 mL). The mixture was stirred at 75° C. for 2 h. The reaction mixture was filtered to give 21 (5.68 g, 84% yield).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([C:21]4[CH:22]=[CH:23][C:18]([O:17][C:16]([F:15])([F:30])[F:31])=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: FC(F)(F)Oc1ccc(C2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-trifluoromethoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 76% overall yield. FDMS m/e=434 (M+ of free base). α[D]589=−13.45 (c=1.04, methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][C@@H:9]([C:18]([OH:20])=[O:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[CH3:23][O:19][C:18](=[O:20])[C@H:9]([CH2:8][C:7]1[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.1 %

Procedure:
To suspesion of of 4-nitro-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine (226.2 mmol, 70.2 g) and sodium carbonate (1.13 mol, 95 g) in DMF (500 mL) was added methyl iodide (1.13 mol, 70.4 mL) at room temperature. The suspesion was stirred for 15 h at room temperature at this time TLC analysis of the mixture indicated the absence of starting acid and the excess methyl iodide and some DMF were removed under high vacuum. The residue was poured into water (2 L) and stirred at room temperature as a precipitate formed slowly over 72 h. The precipitated solids were collected by filtration and washed with water (2 L). After air and vacuum drying, 72 g (98%) of a light yellow solid, mp 95-96° C. were obtained. 1H-NMR, (DMSO-d6) (400 MHz) δ 8.16 (d, 2H, J=20 Hz), 7.53 (d, 2H, J=20 Hz), 7.39 (d, 1H, J=22 Hz), 4.26-4.28 (m, 1H), 3.6 (s, 3H), 2.96-3.19 (m, 2H), 1.25 (s, 9H). 13C NMR, CDCl3 (100 Mhz) δ 172.04, 155.29, 146.27, 145.96, 130.48, 123.18, 78.36, 54.44, 51.9, 36.1, 27.99. HR MS: Obs. mass, 325.1404. Calcd. mass, 325.1400 (M+H).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:13]1=[CH:19][C:20](=[N:27][C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[N:21]([CH2:24][CH2:25][NH2:26])[C:22](=[O:23])[N:12]1[CH2:11][CH2:10]2.Cl.[OH-].[Na+]>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:13]1=[CH:19][C:20](=[N:27][C:28]3[C:29]([CH3:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=3[CH3:34])[N:21]([CH2:24][CH2:25][NH:26][C:2](=[O:1])[NH2:3])[C:22](=[O:23])[N:12]1[CH2:11][CH2:10]2
Reactant: N#C[O-]
Reactant: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCN)c(=O)n1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCNC(N)=O)c(=O)n1CC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Sodium cyanate (6.0 g, 0.092 mol) in water (100 ml) was added dropwise to a stirred solution of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one, prepared according to Preparation 4 above (20.0 g, 0.046 mol) in water (600 ml) and 1N HCl (92 ml) at 80° C. After stirring for 2 h at 80° C. the mixture was cooled in an ice-bath and basified with 2N NaOH. The mixture was extracted with dichloromethane (3×200 ml) and the combined extract was dried (MgSO4) and evaporated in vacuo. The resulting yellow foam was purified by column chromatography on silica gel eluting with CH2Cl/MeOH (97:3) and triturated with ether to obtain the title compound as a yellow solid, 11.9 g, 54%.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>O.CC(C)=O>[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:5]2[C:4]([NH:14][C:13]3[CH:15]=[CH:16][C:10]([Cl:9])=[CH:11][CH:12]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Oc1cccnc1O
Reactant: Nc1ccc(Cl)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1C=C(Nc2ccc(Cl)cc2)C(Nc2ccc(Cl)cc2)=NC1=O
Reaction time: 2 h
Yield: 42 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), p-chloroaniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. It was then filtered and recrystallized with chloroform. The final product was 5,6-di(p-chlorophenylamino)-2,3-pyridindione in a yellow powder. The yield was 42%-60%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a solution of 4-bromo-2-ethyl-benzoic acid (115 mmol) in anhydrous THF (380 mL) at 0° C. was added BH3.THF complex (1.0 N solution in THF, 230 mL) over 30 min. The resulting mixture was slowly warmed up to room temperature and the stirred for 15 hours. The reaction was carefully quenched with slow addition of water. The solvent was removed and the residue was taken up in EtOAc. The organic layer was washed with 1.0 N HCl, H2O, brine and dried over MgSO4. The solvent was removed to afford the desired product. (22 g, 89% yield). 1H NMR (300 MHz, CDCl3): δ 1.23 (t, J=7.5 Hz, 3 H), 2.64–3.01 (m, 2H), 4.68 (s, 2H), 7.24–7.26 (m, 1H), 7.32–7.36 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[I-].[Na+].[CH2:15](Br)[C:16]#[CH:17].C(N(C(C)C)C(C)C)C>CC(C)=O>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:17][C:16]#[CH:15])=[CH:9][C:6]=1[CH:7]=[O:8])([O-:12])=[O:11]
Reactant: C#CCBr
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A mixture of 25 g (150 mmol) 5-hydroxy-2-nitro-benzaldehyde, 44.9 g (299 mmol) sodium iodide, 44.5 g propargyl bromide (80% in toluene), 42 ml N-ethyl-diisopropy-lamine and 400 ml acetone is stirred at rt for 6 d. The reaction mixture is filtered, concentrated, taken up in 1M aqueous hydrochloric acid and extracted with ethyl acetate to yield 2-nitro-5-propargyloxy-benzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]2)=[N:6][CH:7]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:21][CH:18]3[CH2:20][CH2:19]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc(Br)cn2)C1
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(N2CC[C@@H](NC3CC3)C2)nc1
Reaction time: 6 h
Yield: 61.2 %

Procedure:
Dissolve methanesulfonic acid (S)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl ester (3.07 g, 9.48 mmol) and cyclopropylamine (1.7 mL, 23.68 mmol) in THF (20 mL). Microwave the mixture at 130° C. for 6 h. Dilute the mixture with EtOAc (100 mL) and wash with saturated NaHCO3 (25 mL). Dry the organic portion over Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with a gradient of 75-100% EtOAc/hexane to give 1.638 g (61%) of the title compound. LC-MS/ES m/z (79Br) 283.0 [M+H]+.
Reaction SMILES: C(OP([CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10]1)(=O)OCC)C.[CH2:20]=O.O.C[O-].[Na+]>CO>[CH2:20]=[C:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10]1
Reactant: CCOP(=O)(OCC)C1Sc2ccccc2NC1=O
Reactant: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1Sc2ccccc2NC1=O
Temperature: 0 °C
Yield: 72 %

Procedure:
(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-phosphonic acid diethyl ester (12.2 mmol) is dissolved in 40 mL of anhydrous MeOH and formaldehyde (37%) in water (12.2 mmol) is added to the orange solution. NaOMe (2N in MeOH) (12.2 mmol) is added and the reaction is cooled down to 0° C. The solid that precipitates is filtered to give 2-methylene-4H-benzo[1,4]thiazin-3-one. Yield: 72%. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 7.06 (m, 2H), 6.94 (m, 1H), 6.81 (m, 1H), 6.80 (s, 1H), 5.62 (s, 1H). MS: (ES+): 178.2 [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:18][CH:19]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(COC(=O)N2CCC(CNc3ncc(F)cn3)CC2)cc1

Procedure:
The solution of (4-methyl-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2a) (0.20 g, 0.76 mmol), 2-chloro-5-fluoro-pyrimidine (EXAMPLE 71, Step 1) (0.10 g, 0.76 mmol) and triethylamine (0.21 mL, 1.53 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (10 CH2Cl2:1-10 IPA:89-80 hexane) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-methyl-benzyl ester. M.S.(M+1):359.33
Reaction SMILES: C(COC)OC.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Na+].Br[CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>CCOCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:19][C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[C:22]#[N:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: N#Cc1ccccc1CBr
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: N#Cc1ccccc1CS(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A dimethoxyethane (5 ml) suspension of sodium 4-chlorobenzenesulfinate (218 mg, 1.10 mmol) and 2-bromomethylbenzonitrile (215 mg, 1.10 mmol) was stirred at 70° C. for 17 hours. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a short silica gel column and the fraction obtained from the ether eluate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and the fraction obtained from the hexane:ethyl acetate (=3:1) eluate was concentrated under reduced pressure to give a white solid. The resulting white solid was washed with ether, and collected by filtration, whereby the title compound (226 mg, 70%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][N:27]4[C:31](=[O:32])[C:30]5=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]5[C:28]4=[O:37])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (6.44 g, 29.1 mmole), K2CO3 (6.4 g, 46 mmol), N-(3-bromopropyl)phthalimide (8.4 g, 31 mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. The insolubles were filtered. The solvent was removed at reduced pressure and the residue was purified by silica gel column chromatography to give N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimide as a white solid. Recrystallization from ethanol yielded 9.8 g (83%) of off-white crystals, m.p.=129°-130° C.