Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C@@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][O:13][CH3:14])=[CH:5][C:4]=1[NH:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1)#[N:2].C([O-])([O-])=[O:31].[K+].[K+].OO>CS(C)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C@@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH2:12][O:13][CH3:14])=[CH:5][C:4]=1[NH:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1)(=[O:31])[NH2:2]
Reactant: COC[C@@H](CNc1ccc(C#N)c(Nc2cc(C)ns2)c1)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC[C@@H](CNc1ccc(C(N)=O)c(Nc2cc(C)ns2)c1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
The above mentioned crude oil from step 2 was dissolved in DMSO (2 mL), K2CO3 (500 mg, 3.6 mmol) was added; then H2O2 (50% aq., 2 mL) was added dropwise (gas evolved). The mixture was stirred at 80° C. for 15 min, cooled and was diluted with water, the resulting precipitate was collected by filtration, dried in vacuo to give (R)-tert-butyl 1-(4-carbamoyl-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-methoxypropan-2-ylcarbamate as solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=C[N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=N[N:39](CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:39][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Yield: 93 %

Procedure:
5-Benzyloxy-2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1d employing 5-benzyloxy-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 5a) instead of preparation 1c.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17](O)=[O:18])[CH:10]([O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:42][C:17]([C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH:22]=[CH:21][CH:20]=1)=[O:18])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)C(OCc2ccc3ccccc3c2)C1
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)NCc3ccccc3)c2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 36(b), by condensing (3RS,4RS)-3-(1 -tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzoic acid with benzylamine using 1,1-carbonyidiimidazole as the condensation agent there was obtained tert-butyl (3RS,4RS)-4-(3-benzylcarbamoyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 551 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](Cl)=[O:12]>ClCCl>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:11]([C:7]1[O:6][CH:10]=[CH:9][CH:8]=1)=[O:12]
Reactant: CNCCO
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Product: CN(CCO)C(=O)c1ccco1
Yield: 59.1 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 115 g of 2-(methylamino)ethanol (1.53 mol.) and 500 ml of dichloromethane. The reaction flask was cooled with an ice bath. Next, 100 g of furoyl chloride (0.77 mol.) was slowly added via the addition funnel over 2.5 hours. The dichloromethane was washed with NaCl(aq.). Next, the NaCl(aq.) layer was extracted with dichloromethane and the two dichloromethane layers were combined and dried over MgSO4. The dichloromethane was removed with a rotoevaporator to yield 77 g (44%) of N-(2-hydroxyethyl)-N-methylfuranamide.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)(=[O:3])[CH3:2].[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH3:28])=[CH:26][CH:25]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)(=[O:3])[CH3:2]
Reactant: Cc1ccc(CBr)cc1
Reactant: CC(=O)OCc1cc2cc(OCc3ccccc3)ccc2[nH]1
Product: CC(=O)OCc1cc2cc(OCc3ccccc3)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from [5-(benzyloxy)-1H-indol-2-yl]methyl acetate and 4-methylbenzyl bromide in substantially the same manner, as described in step 3 of Example 4. The product was obtained as a white solid. Mass-spectrum (ESI, [M+H)+) m/z 400. 1H NMR (300 MHz, DMSO-d6) δ 7.45 (d, 2H, J=8.34 Hz), 7.37 (t, 2H, J=7.19 Hz), 7.31 (d, 1H, J=7.30 Hz), 7.26 (d, 1H, J=7.56 Hz), 7.15 (d, 1H, J=2.44 Hz), 7.07 (d, 2H, J=8.76 Hz), 6.85 (d, 2H, J=8.81 Hz), 6.84 (s, 1H), 6.25 (s, 1H), 5.35 (s, 2H), 5.17 (s, 2H), 5.09 (s, 2H), 2.22 (s, 3H), 1.84 ppm (s, 3H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:35])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]([OH:34])=[O:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:43][CH3:44].O>CN(C)C=O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:35])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]([O:34][CH2:43][CH3:44])=[O:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C(=O)O)c1Cl)(c1ccccc1)c1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccn1-c1ccc(Cl)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1Cl
Temperature: 60 °C
Reaction time: 16 h
Yield: 103.4 %

Procedure:
A mixture of 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-carboxypyrrole (1.12 g), potassium carbonate (360 mg) and iodoethane (490 mg) in N,N-dimethylformamide (10 ml) was stirred for 16 hours at 60° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, water and brine and dried over magnesium sulfate. The solvent was evaporated to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-ethoxycarbonylpyrrole (1.22 g) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[OH:23]>CN(C=O)C.O>[Br:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 115 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
18.2 g (0.13 mol.) of potassium carbonate and 18.74 g (13.03 ml, 0.11 mol.) benzyl bromide is added to 2-bromo-4-chlorophenol (1) (25 g, 0. 12mol) in DMF (25 ml) under nitrogen. The reaction mixture is heated (oil bath temperature 115° C.) for 1.5 hours and then allowed to cool and left to stand overnight at RT. The reaction mixture is diluted with distilled water (100 ml) and then extracted with Et2O (2×100 ml). The organic extracts are combined, washed with 1M sodium hydroxide (100 ml) and concentrated in vacuo to leave a colorless oil. This oil is purified by flash chromatography (SiO2, pentane) to yield a colorless oil which crystallised on standing to give the title compound as a colorless solid, (29.14 g, 81%), m.p. 49-50.5° C. δH (250 MHz, CDCl3), 7.55 (d, J=2.6 Hz, 1H), 7.46 (m, 5H), 7.19 (dd, J=8.9, 2.5 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.13 (s, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][N:5]1[C@H:10]([C:11]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.C(O)CO>O>[CH3:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]([C:11]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCCCN1CCCC[C@H]1C(=O)Nc1c(C)cccc1C
Solvent: OCCO
Solvent: O
Product: CCCCN1CCCCC1C(=O)Nc1c(C)cccc1C
Temperature: 138 °C

Procedure:
A mixture of (S)-bupivacaine (>99% ee, 1.5 g mmol), ethylene glycol (13.5 ml) and water (1.5 ml) was heated at 138° C. for 9 hours. On cooling to ambient temperature crystallisation of a solid occurred. The solid was filtered to give a quantitative yield of bupivacaine which was shown by chiral HPLC analysis to be a 52:48 mixture of (S)-bupivacaine and (R)-bupivacaine.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:43])[CH2:4][O:5][C:6]([CH2:8][N:9]([S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)(=[O:32])=[O:31])[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[NH:23])=[CH:20][CH:19]=3)=[N:16][C:12]=2[CH:11]=1)=[O:7].Cl[C:45]([O:47][CH3:48])=[O:46]>CC(C)=O.O>[CH3:2][CH:3]([CH3:43])[CH2:4][O:5][C:6]([CH2:8][N:9]([S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)(=[O:32])=[O:31])[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH2:24])=[N:23][C:45]([O:47][CH3:48])=[O:46])=[CH:25][CH:26]=3)=[N:16][C:12]=2[CH:11]=1)=[O:7]
Reactant: CC(C)COC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)N=C(N)c1ccc(Cc2nc3cc(N(CC(=O)OCC(C)C)S(=O)(=O)c4cccc5cccnc45)ccc3n2C)cc1

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-(2-methylpropyloxycarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and methyl chloroformate in acetone/water.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CCN(CC)CC.[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:35]1([C:41]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:17]=[C:16]([NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]5)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)N5CCOCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and morpholine-4-carbonyl chloride (51 μL, 0.44 mmol) in CH2Cl2 (2 mL) was added Et3N (61 μL, 0.44 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of morpholine-4-carbonyl chloride and Et3N were added. After 2 h of stirring another 2 equivalents of both the chloride and Et3N were added and continued to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (12:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(morpholine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (80 mg, 65%)
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([C:24]1[CH:23]=[N:22][C:21]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:11])[CH2:17][CH2:16]2)=[N:26][CH:25]=1)[CH3:28]
Reactant: CCc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 150 °C

Procedure:
The stirred reaction mixture of (1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methylamine (EXAMPLE 154, STEP 2) (0.100 g, 0.387 mmol), 2-chloro-5-ethyl-pyrimidine ([111196-81-7], 0.055 g, 0.387 mmol) and cesium carbonate (0.252 g, 0.774 mmol) in DMF (5 mL) was heated at 150° C. for 7 h. The reaction mixture was cooled to RT, diluted with ethyl acetate (100 mL), washed with water (5×20 mL), and brine (10 mL), then dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60, eluting with 10:1–20:89–70 CH2Cl2:2-propanol:hexane to give the title compound. M.S. (M+1): 365.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([C:30]1[N:31]=[C:32]([CH3:42])[N:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH:34]=1)#[CH:29]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:29]#[C:28][C:30]2[N:31]=[C:32]([CH3:42])[N:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH:34]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodopyridine (1.39 g, 5.8 mmol) was dissolved in 50 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (39 mg, 0.15 mmol) and bis(triphenylphosphine)palladium(II)chloride (170 mg, 0.24 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (28 mg, 0.15 mmol) and 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (970 mg, 4.84 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/triethyl amine 1:0:0→10:10:1 gradient) and recrystallized from heptane and ethyl acetate. The desired product was obtained as a white solid (545 mg, 36%), MS: m/e=312.1 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH:13](OC)(OC)OC.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=[CH:13]1.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: COC(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of diamine 248 (1.14 g, 6.80 mmol) in CH2Cl2 (10 mL) was added trimethyl orthoformate (5 mL, 46 mmol, 6.7 eq) (or any other acylating agent of choice, 6 eq) followed by TFA (0.43 mL, 5.6 mmol, 0.8 eq) and the mixture was stirred at room temperature for 2 h. Precipitate was collected by filtration, washed with CH2Cl2 and dried to afford the title compound 249 as TFA salt (1.23 g, 62% yield). 1H NMR: (CDCl3) δ (ppm): 8.57 (d, J=1.8 Hz, 1H), 8.20 (dd, J=1.8, 9.2 Hz, 1H), 8.18 (s, 1H), 7.54 (d, J=9.2 Hz, 1H), 3.94 (s, 3H). LRMS: (calc.) 177.2; (obt.) 178.1 (MH)+.
Reaction SMILES: [CH:1]1([CH2:5][C@H:6]([C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[C:23]([CH3:29])[CH:22]=2)[C:7](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:8])[CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:31]>O1CCOCC1.O>[CH:1]1([CH2:5][C@H:6]([C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[C:23]([CH3:29])[CH:22]=2)[C:7]([OH:8])=[O:31])[CH2:2][CH2:3][CH2:4]1
Reactant: CSc1ccc([C@@H](CC2CCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1C
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc([C@@H](CC2CCC2)C(=O)O)cc1C
Temperature: 110 °C
Yield: 77 %

Procedure:
A solution of (R)-3-cyclobutyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methyl-4-methylsulfanyl-phenyl)-propionamide (300 mg, 0.73 mmol) in dioxane (4 mL) was treated with a 9 N aqueous sulfuric acid solution (2 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (75 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL) and then concentrated. The resulting residue was then dissolved in methylene chloride and concentrated with silica gel (2 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes) to afford (R)-3-cyclobutyl-2-(3-methyl-4-methylsulfanyl-phenyl)-propionic acid (148 mg, 77%): [α]30589=−48.3° (c=0.18, methylene chloride); EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, observed 264.1183; 1H NMR (300 MHz, DMSO-d6) δ 1.47-2.14 (m, 9H, CH and 4×CH2), 2.21 (s, 3H, ArCH3), 2.43 (s, 3H, SCH3), 3.30 (t, J=7.4 Hz, 1H, ArCHCO), 7.05-7.15 (m, 3H, Ar), 12.28 (s, 1H, CO2H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:7]2=[N:6][C:5]=1[CH3:16].[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:19][CH2:18]1.CC(NC(C)C)C>C(O)C>[N:23]1([CH:20]2[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:7]4=[N:6][C:5]=3[CH3:16])[CH2:18][CH2:19]2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Reactant: Cc1nc2n(C)c(C)cn2c(=O)c1CCBr
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: Cc1nc2n(C)c(C)cn2c(=O)c1CCN1CCC(n2ccc3ccccc32)CC1
Yield: 62 %

Procedure:
A mixture of 6-(2-bromoethyl)-1,2,7-trimethyl-1H,5H-imidazo[1,2-a]pyrimidin-5-one (8.85 g), prepared as described in EP-0,378,255, 1-(4-piperidinyl)-1H-indole (2 g) and N-(1-methylethyl)-2-propanamine (1.2 g) in ethanol (100 ml) was stirred and refluxed for 6 hours. The solvent was evaporated and the residue was stirred in water and subsequently extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN/DIPE and the precipitate was filtered off and dried, yielding 2.5 g (62%) 6-[2-[4-(1H-indol-1-yl)-1-piperidinyl]ethyl]-1,2,7-trimethylimidazo[1,2-a]pyrimidin-5(1H)-one (compound 9; mp. 165.7° C.).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:38][CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)=[O:14])=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:21][CH:22]=1
Reactant: NCCc1ccncc1
Reactant: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1cc(C(=O)NCCc2ccncc2)ccc1OCc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
4-(4-fluorobenzyloxy)-3-isobutylbenzoic acid(1.51 g) was dissolved in chloroform(50 ml) and triethylamine(1.38 ml), and then diphenylphosphinic chloride(0.95 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.61 g) added thereto, was stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.74 g of the aimed compound as white crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([CH3:19])([CH3:18])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH:15]([O:14][CH2:13][CH2:12][N:11]1[C:4]2=[N:3][C:2]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][C:10]1([CH3:19])[CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)OCCN1c2nc(Cl)cc(=O)n2CC1(C)C
Reactant: C1COCCN1
Product: CC(C)OCCN1c2nc(N3CCOCC3)cc(=O)n2CC1(C)C
Yield: 60 %

Procedure:
150 mg of 7-chloro-1-(2-isopropoxyethyl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in 2 mL of morpholine are heated with the microwave oven to 80° C. for 45 mins. The crude is purified by flash chromatography on silica gel (CH2Cl2 100% to CH2Cl2/MeOH, 92/8). 0.085 g (yield=60%) of 1-(2-isopropoxyethyl)-2,2-dimethyl-7-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained as a beige solid and including the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[NH:7][N:6]=1.[C:20](Cl)(=[O:23])[O:21][CH3:22]>C(N(CC)CC)C>[CH3:22][O:21][C:20]([N:7]1[C:8]([CH3:14])=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:5]([O:4][C:3]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:2]=2[CH3:1])=[N:6]1)=[O:23]
Reactant: COC(=O)c1c(Oc2cccc(C)c2C)n[nH]c1C
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(Oc2cccc(C)c2C)nn(C(=O)OC)c1C

Procedure:
A mixture of 5.6 g of triethylamine, 13 g of 3-(2',3'-dimethylphenoxy)-5-methyl-4-methoxycarbonyl pyrazole and 100 ml of tetahydrofuran is prepared, and, while stirring and cooling, 4.9 g of methyl chlorocarbonate is dripped in. After stirring for 16 hours, the precipitated hydrochloride is filtered off. The filtrate is concentrated and the residue is recrystallized from ethyl acetate. Melting point: 115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>ClCl>[Cl:1][C:2]1[C:3]([C:4]([NH:6][CH2:7][CH3:8])=[O:5])=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:16])[C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=1
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reactant: O=[N+]([O-])O
Agent: ClCl
Agent: O=S(=O)(O)O
Product: CCNC(=O)c1c(Cl)ccc([N+](=O)[O-])c1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of the amide of example 45 (1.28 g, 5 mmol) in CH2 Cl2 (20 mL) at 0° C. was added dropwise a cold mixture of 70% nitric acid (0.64 mL, 10 mmol) and concentrated sulfuric acid (5 mL) dropwise. The mixture was stirred at 0° C. for 10 min and was poured onto ice. The mixture was extracted with ether, the combined organic layers washed with sat NaHCO3, brine, dried (MgSO4) and concentrated to a solid (1.52 g, 101%). The title compound was obtained by recrystallization from ethyl acetate/hexanes in 83% yield as a white solid. m.p. 147°-149° C.