Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[CH3:9])[CH:5]=[C:4]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:3]=1.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:10]([N:8]([CH3:9])[C:6]2[CH:5]=[C:4]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[CH:3]=[C:2]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:7]=2)[CH3:11])=[CH:13][CH:14]=1
Reactant: Nc1cnccn1
Reactant: C[C@@H](c1ccc(F)cc1)N(C)c1cc(-c2cnn(C)c2)cc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccc(F)cc1)N(C)c1cc(-c2cnn(C)c2)cc(Nc2cnccn2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
60 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine, 18 mg of 2-aminopyrazine, 16 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 24 mg of sodium t-butoxide and 9 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 60 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow oil. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 29 mg of the objective compound as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:14][CH2:15][C@@H:16]([NH:19][C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: Fc1cc(F)cc(N[C@H]2CC[C@@H](Nc3ccnc4cc(Cl)ccc34)CC2)c1

Procedure:
A mixture of example 23A (30 mg, 0.11 mmol), 1-bromo-3,5-difluorobenzene (25 mg, 0.132 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (1.6 mg, 002 mmol) and sodium-tert-btoxide (14 mg, 0.132 mmol) was heated for 15 hours in ethyleneglycoldimethylether, concentrated and the residue was purified with high throughput HPLC system to provide the desired compound as its bis trifluoroacetic acid salt. MS (ESI(+)Q1MS m/z 388 (M+H)+); 1H NMR (300 MHz, DMSO-D6) δ ppm 8.91 (d, 1 H), 8.71 (d, 1 H), 8.55 (d, 1 H), 7.92 (d, 1 H), 7.80 (dd, 1 H), 7.01 (d, 1 H), 6.25 (m, 4 H), 3.86-4.10 (br.s, 1 H), 3.54 (br.s, 1 H), 3.54 (m, 8 H).
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6]([C:8]1[CH:30]=[C:11]2[C:12]([C:16](=[O:29])[NH:17][CH2:18][C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]5)[CH2:20]3)[CH2:26]4)=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1)=O)C>C1COCC1>[C:19]12([CH2:18][NH:17][C:16]([C:12]3[C:11]4[N:10]([N:9]=[C:8]([CH2:6][OH:5])[CH:30]=4)[CH:15]=[CH:14][CH:13]=3)=[O:29])[CH2:26][CH:25]3[CH2:27][CH:21]([CH2:22][CH:23]([CH2:24]3)[CH2:28]1)[CH2:20]2
Reactant: CCOC(=O)c1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccn2nc(CO)cc12
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A 2.0 M solution of LiBH4 in THF (5.8 mL) is added dropwise to a solution of 4-[(adamantan-1-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (2.01 g, 5.27 mmol) and THF (50 mL) at 0° C. under N2. After 10 min, the ice bath is removed. After 3 h, additional 2.0 M solution of LiBH4 in THF (2.0 mL) is added. After 4 h, sat. aq. NH4Cl is added dropwise. The volatiles are removed under reduced pressure. H2O (20 mL) is added and the solids are collected by filtration. The solids are slurried in MeOH (75 mL) and warmed to 50° C. for 4 h. The volatiles are removed under reduced pressure to afford the title compound as a light tan solid. 1H NMR (300 MHz, CDCl3) δ: 8.58 (ddd, 1H), 7.56 (dd, 1H), 6.92 (t, 1H), 6.90 (s, 1H), 4.80 (s, 2H), 3.12 (s, 2H), 1.96-2.04 (m, 3H), 1.62-1.84 (m, 12H). LC-MS m/z (M+H+): 340.3; RT=1.27 min.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[CH3:43][O:44][C:45](=[O:53])[C:46]1[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[CH3:43][O:44][C:45](=[O:53])[C:46]1[CH:51]=[CH:50][C:49]([NH:52][C:36]2[C:37]3[N:38]([N:39]=[CH:40][N:41]=3)[C:33]([Br:32])=[CH:34][N:35]=2)=[CH:48][CH:47]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Nc2ncc(Br)n3ncnc23)cc1

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1 using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (250 mg, 0.90 mmol), 4-aminobenzoic methyl ester (163 mg, 1.08 mmol) and N-ethyldiisopropyl-amine (0.19 mL, 1.08 mmol) in 2-propanol (2.5 mL). The title compound is obtained after trituration with 2-propanol as a brown solid (148 mg, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:15][C:16](=[O:18])[CH3:17])([CH2:13][OH:14])[CH2:11][OH:12])=[CH:4][CH:3]=1.CO[C:21](OC)([CH3:23])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][O:12][C:21]([CH3:23])([CH3:22])[O:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: CC(=O)NC(CO)(CO)CCc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)NC1(CCc2ccc(Br)cc2)COC(C)(C)OC1
Yield: 87.3 %

Procedure:
A solution of N-[3-(4-bromophenyl)-1,1-bis(hydroxymethyl)propyl]acetamide (42.2 g) of Reference Example 4, acetone dimethyl acetal (41.9 g) and a catalytic amount of p-toluenesulfonic acid in acetone (200 mL) was stirred at room temperature for one day. The reaction mixture was concentrated under reduced pressure, and the residual crude crystals were suspended in aqueous sodium hydrogen carbonate solution and collected by filtration to give the title compound (41.5 g) as white crystals.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Yield: 92.6 %

Procedure:
To a solution of tert-butyl (3R)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 12 (0.28 g, 0.59 mmol) in methanol (20 mL) was added 5% Pd/C (0.25 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl (3R)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 13 (0.21 g, 91%) as a white solid.
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[CH:10]([N:23]=[C:24]=[S:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:10]([N:23]1[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:24]1=[S:25])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: S=C=NC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CC(=O)N(C(c2ccccc2)c2ccccc2)C1=S
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), benzhydryl-isothiocyanate (11.25 g), triethyl amine (12 g) and chloroform (200 mL) was heated at reflux for 5 hours. The mixture was cooled to ambient temperature, washed with 1N HCl (2×200 mL), then with water (200 mL) The organic phase was evaporated to dryness. The residue was crystallized from ethanol to give the title compound (7.40 g) as an off-white solid, m.p. 139°-141° C. Anal. Calcd. for C17H16N2O S: C, 68.89; H, 5.44; N, 9.45. Found: C, 68.92; H, 5.43; N, 9.58. Mass spectrum (EI, M.+) m/z 296.
Reaction SMILES: CS[C:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:17])[N:4]=1.[OH-].[NH3:19]>>[NH2:19][C:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:17])[N:4]=1
Reactant: CCCCCn1c(SC)nc(=O)c2[nH]cnc21
Reactant: N
Agent: [OH-]
Product: CCCCCn1c(N)nc(=O)c2[nH]cnc21
Temperature: 100 °C
Reaction time: 96 h
Yield: 68 %

Procedure:
2-(Methylthio)-3-pentyl-3,7-dihydro-6H-purin-6-one (5.0 g, 0.020 mol) was mixed with 100 ml of 28% ammonia hydroxide in a seal tube. The mixture was stirred at 100° C. for 4 days. After cooling to room temperature, the solid was filtered and dried to yield the desired product (3.0 g, 68%). LCMS calculated for C10H16N5O (M+H): 222.1. Found: 222.1.
Reaction SMILES: [OH:1][C:2]1[C:13]2[C:12](=[O:14])[O:11][CH2:10][C:9]3[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([O:19][CH3:20])[C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25].C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1>[OH:1][C:2]1[C:13]2[C:12](=[O:14])[O:11][CH2:10][C:9]3[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([O:19][CH3:20])[C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH:22]([OH:27])[CH2:23][CH:24]([CH3:25])[CH3:26]
Reactant: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(O)c1C(=O)OC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C)cc2c1Oc1ccc(C(O)CC(C)C)c(O)c1C(=O)OC2
Reaction time: 14 h

Procedure:
2.2 g (5.9 mmol) of the compound from Example 109 are dissolved in 40 ml of tetrahydrofuran, and 7 ml of glacial acetic acid and 0.96 g (15 mmol) of sodium cyanoborohydride are added. After 14 h at room temperature, the mixture is concentrated in vacuo, the residue is taken up in dichloromethane, and the solution is washed with sodium hydrogen carbonate solution and water, dried over magnesium sulphate and concentrated in vacuo. Purification is carried out by column chromatography on silica gel using dichloromethane/methanol 150/1 as the eluent.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH:14]1[C:19]([CH2:20][CH:21]([NH2:25])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=[C:16]([F:26])[CH:15]=1>>[F:26][C:16]1[CH:15]=[CH:14][C:19]([CH2:20][CH:21]([NH:25][C:11]([C:10]2[C:6]3[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=3[S:8][CH:9]=2)=[O:13])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NC(Cc1ccc(F)cc1)C(=O)O
Reactant: O=C(O)c1csc2c1CCCC2=O
Product: O=C(NC(Cc1ccc(F)cc1)C(=O)O)c1csc2c1CCCC2=O

Procedure:
From 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (the compound of Preparation Example 4) (105 mg) and DL-4-fluorophenylalanine, the title compound (190 mg) was obtained as a viscous yellow oily substance, in the same way as Preparation Example 116.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[S:12]([C:15]1C=C(C=CC=1C)C(O)=O)(=[O:14])=[O:13].ClC1C=C(Cl)C(S(Cl)(=O)=O)=CC=1C(O)=O>ClS(O)(=O)=O>[CH3:15][S:12]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[CH3:1])[C:6]([OH:8])=[O:7])(=[O:14])=[O:13]
Reactant: Cc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=C(O)c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Agent: O=S(=O)(O)Cl
Product: Cc1ccc(C(=O)O)cc1S(C)(=O)=O

Procedure:
4-Methylbenzoic acid (0.2 mole) is added to chlorosulfonic acid (50 ml.) and heated at reflux for about one hour, cooled and poured onto ice. The product, 3-chlorosulfonyl-4-methylbenzoic acid that separates is then employed in place of the 2,4-dichloro-5-chlorosulfonylbenzoic acid in the process described in Example 1, Step A, and then following the methods described in Steps A and B of Example 1 there is obtained 3-methylsulfonyl-4-methylbenzoic acid. This compound then is substituted for the 3-methylsulfonyl-4-chlorobenzoic acid employed in Step B of Example 55 and then by following substantially the same procedures described in Example 55, Steps B through E, there is obtained 3-furfurylamino-4-methyl-5-methylsulfonylbenzoic acid.
Reaction SMILES: [NH:1]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:2]([C:13]([NH:15][C@H:16]([C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([O:38]CC1C=CC=CC=1)=[O:37])=[O:33])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C1COCC1>[NH:1]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[C@H:2]([C:13]([NH:15][C@H:16]([C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([OH:38])=[O:37])=[O:33])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][CH:19]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A solution of 3.60 g of BOC-Thr(Bzl)-Tyr(Bzl)-Pro-OBzl dissolved in 20 ml of THF was mixed under cooling and stirring with 5.83 ml of 1N sodium hydroxide, and the mixture was stirred at room temperature for 3 hours. Then, 1N hydrochloric acid was added to adjust pH to 7, and the mixture was concentrated under reduced pressure to evaporate THF. The residual aqueous solution was diluted with water, washed with diethyl ether, then adjusted to pH 2 with addition of 1N hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diethyl ether-n-hexane to obtain a crude product. Recrystallization of this product from ethyl acetate-diethyl ether-n-hexane gave 2.15 g (yield: 67.8%) of BOC-Thr(Bzl)-Tyr(Bzl)-Pro-OH melting at 134° to 137° C. Rf1 =0.46, Rf3 =0.24.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][CH2:11][OH:12])=[C:5]([CH3:13])[N:4]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:1][S:2][C:3]1[N:8]([CH3:16])[C:7](=[O:9])[C:6]([CH2:10][CH2:11][OH:12])=[C:5]([CH3:13])[N:4]=1
Reactant: CSc1nc(C)c(CCO)c(=O)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(C)c(CCO)c(=O)n1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-methylthio-5-(2-hydroxyethyl)-6-methyl-3H-pyrimidin-4-one (34 g, 0.17 mol) in DMF (300 ml) was added slowly one equivalent of sodium hydride (55%, 7.4 g). Next was added slowly one equivalent of methyl iodide (10.5 ml). The mixture was stirred for two hours at 50° C., after which most of the DMF was removed in vaccuum. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated and purified by flash chromatografy (eluens: ether followed by ether/methanol=9/1). Yield 20.3 g (56%), mp. 117-118° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])[CH2:5][CH2:6][Cl:7].[NH3:23]>CCOCC>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12]([NH2:23])=[O:13])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])[CH2:5][CH2:6][Cl:7]
Reactant: N
Reactant: O=C(O)c1cc([N+](=O)[O-])c(N(CCCl)CCCl)c([N+](=O)[O-])c1
Solvent: CCOCC
Product: NC(=O)c1cc([N+](=O)[O-])c(N(CCCl)CCCl)c([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
The above acid (XV: X=Cl, Z=OH) was converted to the crude acid chloride (XV: X=Cl, Z=Cl), which was dissolved in dry Et2O (100 mL), cooled to 5° C., and treated dropwise with aqueous NH3 (20 mL of a 3N solution, 60 mmol). After 10 min the solution was worked up, and the residue was chromatographed on silica. Elution with EtOAc/petroleum ether (3:7) gave foreruns, while EtOAc/petroleum ether (7:3) gave 4-[N,N-bis(2-chloroethyl)amino]-3,5-dinitrobenzamide (23) (Ig: X=Cl, R=CONH2) (80% overall yield), mp (EtOAc/petroleum ether) 113°-116° C. 1H NMR (CD3COCD3) δ 8.61 (s, 2 H, H-2,6), 7.98, 7.24 (2xbr, 2 H, CONH2), 3.75 (t, J=7.0 Hz, 4 H, CH2Cl), 3.50 (t, 4 H, CH2N). 13C NMR δ 164.91 (CONH2), 149.32 (C-4), 140.07 (C-3,5), 132.18 (C-1), 128.91 (C-2,6), 56.37 (CH2N), 42.55 (CH2Cl). Anal. (C11H12Cl2N4O5) C,H,N,Cl.
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH2:5][CH2:6][CH:7](C)C)[C:3]#[CH:4].CN(C=O)C.[CH3:16]CN(CC)CC.FC(F)(F)S(O[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])(=O)=O>CCOC(C)=O>[C:32]([Si:29]([O:10][C:2]([CH2:5][CH:6]([CH3:7])[CH3:16])([CH3:1])[C:3]#[CH:4])([CH3:31])[CH3:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C#CC(C)(O)CCC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CC(C)(CC(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.9 %

Procedure:
An oven-dried flask was charged with 3,6-dimethyl-1-heptyn-3-ol (1.0 g, 0.007 mol) and dry DMF (7.0 mL). To this solution, cooled in an ice bath, was added Et3N (3.6 mL, 0.025 mol) followed by dropwise addition of tert-butyldimethylsilyl trifluoromethanesulfonate (2.5 g, 0.014 mol) under nitrogen atmosphere. The resulting mixture was stirred at RT for 18 h and then diluted with EtOAc (80 mL). The organic layer was washed with saturated solution of NH4Cl (30 mL), water (4×20 mL), brine (40 mL), dried over sodium sulfate, and evaporated to afford the desired compound (1.8 g), as a yellow oil, used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.15 (s, 6H), 0.88-0.84 (m, 15H), 1.38-1.29 (m, 1H), 1.42 (s, 3H), 1.54-1.48 (m, 2H), 1.62-1.55 (m, 2H), 2.38 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([O:25]C)=O)=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[CH2:12][CH2:13][N:7]21.[CH:27]1([Mg]Br)[CH2:29][CH2:28]1.O.O1[CH2:37][CH2:36][CH2:35]C1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([C:23]([CH:35]2[CH2:36][CH2:37]2)([CH:27]2[CH2:29][CH2:28]2)[OH:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Reactant: Br[Mg]C1CC1
Reactant: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(Cl)c1N1CCn2c1nc1c(Cl)ccc(C(O)(C3CC3)C3CC3)c12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 30 %

Procedure:
To a solution of methyl 8-chloro-1-(2,4-dichloro-6-methylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole-5-carboxylate (90 mg, 0.219 mmol) in tetrahydrofuran (2.2 mL) was added a solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.0 M, 1.3 mL, 1.3 mmol) at room temperature. The mixture was stirred at 60° C. for 1.5 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-60% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate to give the title compound (29.9 mg, 0.065 mmol, 30%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:11]=2[O:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[Cl:21])[C:5]([O:7][CH3:8])=[O:6])(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.13 g of methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in a mixture of toluene/pyridine (20 ml/30 ml) treated dropwise while cooling with ice with a solution of 1.05 g of 4-tert.butyl-benzenesulphonyl chloride in toluene (30 ml) and subsequently stirred at RT for 24 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 3-(4-tert-butyl-benzenesulphonylamino)-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a yellow solid.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([C:12]([O-:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([O-:9])=[O:8].S(=O)(=O)(O)O>O>[Cl:2][C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C([O-])c1ccc(Cl)cc1C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1C(=O)O

Procedure:
To a suspension of 750 g of monosodium-4-chlorophthalate and 1200 ml water was added 120 ml conc. sulfuric acid. The resulting brown solution was extracted with three 400 ml portions of ether. The combined extracts were treated with carbon black, filtered and the ether distilled. The 4-chlorophthalic acid obtained was dehydrated by heating to 170°C for two hours to give 548 g of anhydride. To a solution of the anhydride in 2250 ml of xylene was added 279 g of aniline diluted with an equal weight of xylene. The solution was refluxed for 16 hours and the water formed was collected in a Dean-Stark trap. After treatment with carbon black the hot xylene solution was cooled to 5°C to give 475 g of crude 4-chloro-N-phenyl phthalimide. Recrystallization from 2000 ml toluene, twice, provided 364 g of 92% pure imide.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][CH:33]4[CH2:35][CH2:34]4)=[O:31])=[CH:25][C:24]=3[F:36])[CH:14]=2)=[CH:9][CH:8]=1.CC(O)=O.O>O>[CH:33]1([NH:32][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:10]5[CH:11]=[N:12][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=5)[S:21][C:20]=34)=[C:24]([F:36])[CH:25]=2)=[O:31])[CH2:34][CH2:35]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)nc4)sc23)c(F)c1)NC1CC1
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cn1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A solution of 281 (2.71 mg, 5.35 mmol) in a mixture AcOH/water (32 mL/8 mL) was heated at 90° C. for 29 h. After cooling to RT the reaction mixture was diluted with water to form a precipitate that was collected by filtration and dried under vacuum to afford the title compound 282 (2.25 g, 5.02 mmol, 94% yield) as a brown solid. MS (m/z): 449.2 (M+H).