Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:18]([O-])([O-])[O:19][CH2:20][CH3:21].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([C:6](=[CH:18][O:19][CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Br
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Br
Temperature: 150 °C
Yield: 79.7 %

Procedure:
A mixture of ethyl (2-bromo-4,5-difluorobenzoyl)acetate (52.0 g), ethyl orthoformate (36.6 g) and acetic anhydride (41.6 g) is heated at 150° C. for 2 hours. After the reaction, the reaction mixture is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:n-hexane=2:1) to give ethyl 2-(2-bromo-4,5-difluorobenzoyl)-3-ethoxyacrylate (49 g).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:25]#[N:26])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])C.[NH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>CN(C=O)C.O>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:7]=[C:8]2[C:25]#[N:26])=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(N)CC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2cc(OCc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)O)NC(=O)c1nc(C#N)c2cc(OCc3ccccc3)ccc2c1O
Temperature: 140 °C
Yield: 92 %

Procedure:
7-Benzyloxy-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (US Patent Publication No. 2007/627906) (40 mg, 0.115 mmol) was dissolved in anhydrous DMF (2 mL). 3-Amino-3-methyl-butyric acid (68 mg, 0.5742 mmol) and solid sodium methoxide (25 mg, 0.459 mmol) were added sequentially and the mixture heated to 140° C. in an oil bath for 3.5 h. Upon completion, the reaction mixture was cooled and diluted with water. The solution was acidified to pH 3 with 1M hydrochloric acid inducing precipitation of the product. The free acid was isolated by filtration and dried to provide the title compound as a tan solid in 92% yield. MS ESI(−) m/e: 417.9596 (M−1), MS ESI(+) m/e: 419.9934 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:20]>ClCCl>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:20]
Reactant: CNCCN1CCOCC1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)N(C)CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of N-methyl-2-morpholinoethanamine (2.1 g, 13.12 mmol, 1.00 equiv, 90%) in dichloromethane (20 mL) at 0-5° C. was added triethylamine (1.47 g, 14.55 mmol, 1.00 equiv) followed by dropwise addition of a solution of methyl 3-(chlorocarbonyl)benzoate (3.3 g, 15.00 mmol, 1.20 equiv, 90%) in dichloromethane (10 mL). The resulting solution was then stirred for 3 h at room temperature. The mixture was diluted with 100 mL of dichloromethane, washed with 1×30 mL of 10% sodium bicarbonate and 1×30 mL of brine, dried over sodium sulfate and then concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (20:1) to afford 4.4 g (99%) of methyl 3-(methyl(2-morpholinoethyl)carbamoyl)benzoate as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 21 %

Procedure:
To a stirred solution of methyl 3,5-dihydroxybenzoate (5.95 mol) in DMF (6 L) was added potassium carbonate (9 mol), and the suspension stirred at ambient temperature under argon. To this was added benzyl bromide (8.42 mol) slowly over 1 hour, with a slight exotherm, and the reaction mixture stirred overnight at ambient temperature. The reaction was quenched cautiously with ammonium chloride solution (5 L) followed by water (35 L). The aqueous suspension was extracted with DCM (1×3 L and 2×5 L). The combined extracts were washed with water (10 L) and dried overnight (MgSO4). The solution was evaporated in vacuo, and the crude product chromatographed in 3 batches (flash column, 3×2 kg silica, eluting with a gradient consisting of hexane containing 10% DCM, to neat DCM, to DCM containing 50% ethyl acetate) to eliminate starting material. The crude eluant was further chromatographed in 175 g batches (Amicon HPLC, 5 kg normal-phase silica, eluting with isohexane containing 20% v/v of ethyl acetate) to give the desired compound (21% yield). 1H NMR δ (d6-DMSO): 3.8 (s, 3H), 5.1 (s, 2H), 6.65 (m, 1H), 7.0 (m, 1H), 7.05 (m, 1H), 7.3-7.5 (m, 5H), 9.85 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:28])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C@:15]3([CH3:27])[C:21]([F:23])([F:22])[C:20]([CH3:25])([CH3:24])[O:19][CH2:18][C:17](=O)[NH:16]3)[CH:9]=2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:28])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C@:15]3([CH3:27])[C:21]([F:23])([F:22])[C:20]([CH3:25])([CH3:24])[O:19][CH2:18][C:17](=[S:38])[NH:16]3)[CH:9]=2)[CH:7]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cc(F)cc(Cl)c3)ccc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cc(F)cc(Cl)c3)ccc2F)C1(F)F
Yield: 96.9 %

Procedure:
The reaction of (R)-5-(5′-chloro-4,3′-difluoro-biphenyl-3-yl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (130 mg, 313 μmol) with Lawesson's reagent (130 mg, 313 μmol) in 1,4-dioxane (5 ml) yielded the (R)-5-(5′-chloro-4,3′-difluoro-biphenyl-3-yl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (131 mg, 97%) as a white foam. MS (ISP): m/z=432.2 [M+H]+ and 434.2 [M+2+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][N:44]1[CH2:49][CH2:48][CH:47](O)[CH2:46][CH2:45]1>>[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:46][CH2:45]1
Reactant: CN1CCC(O)CC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OC2CCN(C)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 1-methylpiperidin-4-ol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-methyl-piperidin-4-yl ester. MS (ES+) m/z calcd. for C37H41Cl2F2N4O4: [(M+H)+]: 713. found: 713.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]=[O:12])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[CH2:14][CH2:15][CH3:16]>>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][CH:5]1[C:11](=[O:12])[CH2:13][CH2:14][CH2:15][CH3:16])([CH3:3])[CH3:2]
Reactant: CCCC[Mg]Br
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C=O
Product: CCCCC(=O)C1C[C@H](C)CC[C@H]1C(C)C

Procedure:
The title compound was prepared following the general procedure of Example 1 starting from (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbaldehyde and butyl magnesium bromide.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:54]([NH:64][C@H:65]([C:70](O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55].N>ClCCl.CO>[C:54]([NH:64][C@H:65]([C:70]([NH:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:71])[CH2:66][CH:67]([CH3:68])[CH3:69])([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Yield: 61 %

Procedure:
from N-(2-L-leucyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-octadecanamide and N-carbobenzoxy-L-leucine. Yield 61%. Rf 0.50 (dichloromethane/methanol/conc. ammonia 15:1:0.1).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](O)=[O:24]>>[CH3:31][O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:21]([O:20][CH3:19])[C:22]=1[C:23]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:24]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: COc1cccc(OC)c1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. for C23H24N4O3, 404.47; m/z found, 405.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[NH2:1][C:2]1[C:7]([S:8]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
2-amino-5-bromopyridine-3-sulfonyl chloride (15 g, 55 mmol) was dissolved in THF (125 mL) and at 0° C. t-butylamine (6.5 g, 111 mmol) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure to yield 2-amino-5-bromo-N-tert-butylpyridine-3-sulfonamide (8.4 g, 49%), which was used without further purification. LCMS Method Y: retention time 1.70 min, [M−1]=306.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([C:15]3[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:12]=[N:11][C:10]=12)=[O:5])C.[OH-].[Na+:26]>C(O)C>[Na+:26].[F:23][C:21]([F:22])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]2[N:9]3[N:8]=[CH:7][C:6]([C:4]([O-:5])=[O:3])=[C:10]3[N:11]=[CH:12][CH:13]=2)[CH:16]=1
Reactant: CCOC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 3.35 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, 20 ml. of 5 N sodium hydroxide and 75 ml. of ethanol is heated on a steam bath for 4 hours. The mixture is cooled and solid is recovered by filtration giving the desired product, m.p. 322°-325° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[C:52]([O:53][CH3:54])=[CH:51][C:49]([NH2:50])=[C:48]([O:55][CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.N>CC(O)C.Cl.CO>[N:34]1([CH:40]2[CH2:41][CH2:42][N:43]([C:46]3[C:52]([O:53][CH3:54])=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=5[F:29])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([O:55][CH3:56])[CH:47]=3)[CH2:44][CH2:45]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)c(OC)cc1N
Agent: Cl
Agent: N
Solvent: CO
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)c(OC)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 40.3 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 4-(1,4′-bipiperidin-1′-yl)-2,5-bis(methyloxy)aniline (0.166 g, 0.520 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (4 drops) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo. The resulting residue was taken up in DCM and purified by column chromatography using basic alumina. The desired combined fractions were concentrated and the resulting solid was triturated with DCM and hexane, filtered and air dried to give the title compound (0.130 g, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.41 (br. s., 1H), 8.50 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.1 Hz, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.43-7.50 (m, 1H), 7.36-7.42 (m, 1H), 7.34 (s, 1H), 7.20 (t, J=8.1 Hz, 2H), 6.94-7.00 (m, 1H), 6.66 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 3.43 (d, J=11.7 Hz, 2H), 2.51-2.58 (m, 2H), 2.26-2.35 (m, 1H), 1.77 (d, J=13.6 Hz, 2H), 1.53-1.64 (m, 2H), 1.48 (s, 4H), 1.38 (s, 2H). MS (M+H, ES+) 745.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 15 g of Piperazine-1-carboxylic acid tert-butyl ester in 200 ml of DCM, 18 g of triethylamine was added and the mixture was cooled to 0° C. Then, 12.1 g of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 16 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1 M aqueous hydrochloric acid followed by saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 21.9 g.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1.[IH:18].C([O-])(O)=O.[Na+]>CCO>[I:18][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1
Reactant: CCOC(=O)c1cc(Br)cc(C(=O)OCC)n1
Reactant: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(I)cc(C(=O)OCC)n1

Procedure:
A mixture of diethyl 4-bromopyridine-2,6-dicarboxylate (8.36 g, 27.7 mmol), 57% (w/w) aqueous hydriodic acid (31.05 g, 138.4 mmol) and EtOH (67 mL) was stirred at 50° C. for 1 h and neutralized with saturated NaHCO3 solution. The product was extracted from the aqueous phase with CH2Cl2 (2×300 mL). The combined organic fractions were dried with Na2SO4 and evaporated to dryness. Yield was 5.24 g (54%). ESI-TOF-MS [M+H]+: calc. for C11H13INO4+ 349.99. found 349.99.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:6]=1[OH:13])(=O)[CH3:2].C([O-])(=O)C.[Na+]>>[CH3:2][C:1]1[O:13][C:6]2[C:7]([Cl:12])=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=2[N:4]=1
Reactant: CC(=O)Nc1cc(Cl)cc(Cl)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1nc2cc(Cl)cc(Cl)c2o1
Yield: 49.3 %

Procedure:
A mixture of 61.8 g of 2-acetylamino-4,6-dichloro-phenol and 4.12 g of anhydrous sodium acetate was heated for some minutes, obtaining a liquid slurry which was distilled under reduced pressure, by collecting the fraction distilled between 145° - 155° C at 1,4 mm Hg. The distilled oil upon standing became a solid which was crystallized from ligroin, obtaining 28 g of 2-methyl-5,7-dichloro-benzoxazole. M.P. = 110° - 113° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:6]1=[O:25].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[O:25]=[C:6]1[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][CH2:3][CH:2]=[O:1]
Reactant: O=C1N(CCCO)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To a solution of 1′-(3-hydroxypropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (4.82 g, 14.2 mmol) in dichloromethane (150 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (7.00 g, 16.7 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 4 h, diluted with ethyl acetate, washed sequentially with 10% Na2S2O3 solution, saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash chromatography and the product was recrystallized from ethyl acetate/hexanes to afford the title compound (3.86 g) in 80% yield: 1H NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 7.33-6.92 (m, 4H), 6.48 (s, 1H), 6.08 (s, 1H), 4.86 (m, 1H), 4.61 (m, 1H), 4.15-3.98 (m, 2H), 2.97-2.84 (m, 2H); MS (ES+, m/z) 338.1 (M+1).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](O)=O)=[N:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:12]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:17][CH:18]=1)[CH2:11][CH2:10][CH3:9]
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCc1ccc(-c2nc3ccccc3[nH]2)nc1
Reaction time: 1.5 h

Procedure:
0.6 g. of o-phenylenediamine, 1 g. of fusaric acid and 10 g. of polyphosphoric acid were heated at 200°-250° C. under nitrogen gas current with stirring for 1.5 hours. The reaction mixture was diluted with 200 ml. of water and then neutralized with sodium carbonate. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate. 1.2 g. of colorless needles of the product (86% of theory) was obtained. M.P. 138.0°-139.0° C.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15]Br)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)C.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OC(=O)C)C>[NH2:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15][N:27]3[CH2:28][CH2:29][CH:24]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CC(=O)Nc1nc2ccc(CCBr)cc2s1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(CCN3CCC(Cc4ccccc4)CC3)cc2s1
Yield: 67 %

Procedure:
A solution of 3 g of 1-(2-Acetylamino-benzothiazol-6-yl)-2-bromo-ethane and 1.95 g of 4- benzylpiperidin and 3.5 g of K2CO3 in 20 ml of DME was heated at 75° C. for 2 hours. The solution was diluted with ethylacetate and washed with brine, after removal of the solvent the residue was heated at reflux in 50 ml of ethanol containing 5 ml of 5 M NaOH for 1 hour. The solvent was evaporated and the residue taken up in ethylacetate was washed with brine and dried. After removal of the solvent, the reaction produce was chromatographed on silica gel eluting with ethylacetate/cyclohexane ⅓ affording the title compound in 67% yield, m.p. 152-153° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.Cl.[CH2:27]([O:29][C:30](=[O:34])[CH2:31][CH2:32][NH2:33])[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([O:29][C:30]([CH2:31][CH2:32][NH:33][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)=[O:34])[CH3:28]
Reactant: CCOC(=O)CCN
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1-c1nc2nc(NCCC(=O)OCC)ncc2c(=O)[nH]1

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.0 g), β-alanine ethyl ester hydrochloride (1.10 g) and triethylamine (0.73 g) in dichloromethane (20 ml) was stirred at ambient temperature for 2.5 hours. The reaction mixture was extracted with dilute hydrochloric acid (20 ml) then water (10 ml), and the extracts back washed with dichloromethane (10 ml). The combined organic extracts were dried (magnesium sulphate) and evaporated under reduced pressure to yield a crude product which was recrystallized from ethanol:water to yield the title compound, 0.83 g, m.p. 142-3° C.