Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:49][C@@H:50]([CH:89]([CH3:91])[CH3:90])[C:51]([O:53][C@H:54]1[C@H:59]([NH:60][C:61]([O:63][CH3:64])=[O:62])[CH2:58][CH2:57][N:56]([C:65]2[CH:70]=[C:69]([C:71]#[N:72])[CH:68]=[C:67]([NH:73][C:74]3[N:79]=[C:78]([NH:80][CH2:81][CH3:82])[C:77]4=[N:83][CH:84]=[C:85]([C:86]#[N:87])[N:76]4[N:75]=3)[C:66]=2[Cl:88])[CH2:55]1)=[O:52]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:49][C@@H:50]([CH:89]([CH3:90])[CH3:91])[C:51]([O:53][C@H:54]1[C@H:59]([NH:60][C:61]([O:63][CH3:64])=[O:62])[CH2:58][CH2:57][N:56]([C:65]2[CH:70]=[C:69]([C:71]#[N:72])[CH:68]=[C:67]([NH:73][C:74]3[N:79]=[C:78]([NH:80][CH2:81][CH3:82])[C:77]4=[N:83][CH:84]=[C:85]([C:86]#[N:87])[N:76]4[N:75]=3)[C:66]=2[Cl:88])[CH2:55]1)=[O:52])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)[C@@H](N)C(C)C)C3)c2Cl)nn2c(C#N)cnc12
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(C)C)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of (S)-2,6-bis((tert-butoxycarbonyl)amino)hexanoic acid (30 mg, 0.087 mmol) in dry DCM (1 mL) was added TBTU (27.5 mg, 0.086 mmol) and TEA (0.030 mL, 0.214 mmol) under N2 atmosphere. The reaction mixture was stirred 0.5 h at the same temperature and (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-amino-3-methylbutanoate dihydrochloride (36.5 mg, 0.053 mmol) was added. The reaction stirred 1 h at room temperature; the LCMS showed complete conversion. The reaction mixture was diluted with DCM, washed with water, and dried over Na2SO4. The solvent was removed and the reaction mixture was taken-up in DCM and purified on a silica gel column: eluting with 10-80% acetone-hexane to afford (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((S)-2,6-bis((tert-butoxycarbonyl)amino)hexanamido)-3-methylbutanoate.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[NH:35]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@@H:36]([C:54]([OH:56])=O)[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:53])[NH:42][S:43]([C:46]1[CH:52]=[CH:51][C:49]([CH3:50])=[CH:48][CH:47]=1)(=[O:45])=[O:44].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:35]([C:57]([O:59][C:60]([CH3:62])([CH3:63])[CH3:61])=[O:58])[C@@H:36]([C:54]([NH:1][C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)=[O:56])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:53])[NH:42][S:43]([C:46]1[CH:47]=[CH:48][C:49]([CH3:50])=[CH:51][CH:52]=1)(=[O:44])=[O:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1

Procedure:
Using 2.32 g Boc-Tyr(Bzl)-OBzl, 2.37 g Boc-D-Arg(Tos)-OH, 0.75 g HONB and 1.14 g DCC, the desired product was obtained in exactly the same manner as in Example 1-(I).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].[NH2:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15]([OH:28])=[CH:14][C:13]=1Cl.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.CN1CCCC1=O>[NH2:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15]([OH:28])=[CH:14][C:13]=1[O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([OH:9])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(O)C(C)(C)CO
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: Oc1ccccc1
Product: CCCC(O)C(C)(C)COc1cc(O)c2c(c1N)C(=O)c1ccccc1C2=O

Procedure:
90 parts of 2,2-dimethyl-1,3-hexanediol, 27.3 parts of 1-amino-4-hydroxy-2-chloroanthraquinone, 45 parts of N-methylpyrrolidone, 9.4 parts of phenol and 12 parts of potassium carbonate are heated for 5 hours at 130°C and 8 hours at 140°C under nitrogen. When cold, the mixture is diluted with 140 parts of methanol and filtered. The filtrate is diluted with water. 21 parts of 1-amino-2-(2',2'-dimethyl-3'-hydroxyhexoxy)-4-hydroxyanthraquinone are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10])=[O:5].CC(C)C([SiH2][O:35][NH2:36])(C)C>>[Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([NH:36][OH:35])=[O:10])=[O:5]
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CC(C)C(C)(C)[SiH2]ON
Product: Cc1ccc(C(=O)NO)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
Compound 424 (202 mg, 0.50 mmol) and O-[(dimethyl-t-butyl)silyl]-hydroxylamine (148 mg, 1.01 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 67/33 to 100/0) provided the title compound. 13C NMR (DMSO-d6) δ 194.6, 162.9, 158.8 (dd), 155.8 (dd), 149.4, 139.5, 139.1, 133.6, 131.1, 130.3, 128.7, 127.0, 126.5 (m), 126.4, 124.1 (dd), 114.8, 111.9 (dd), 111.8, 105.0 (dd), 19.6
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].Br[CH2:14][C:15]([CH3:17])=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:16][C:15](=[CH2:14])[CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: C=C(C)CBr
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=C(C)COc1cccc(C(=O)O)c1

Procedure:
The reaction of Ethyl 3-hydroxyl-benzoate and 3-Bromo-2-methyl-propene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 3-(2-Methyl-allyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.50 (m, 1 arom. H); 7.44 (m, 2 arom. H); 7.19 (m, 1 arom. H); 5.04, 4.96 (2 s, —C(CH3)═CH2); 4.50 (s, CH2—C(CH3)═CH2); 1.75 (s, C(CH3)═CH2). 13C-NMR (100 MHz, d6-DMSO): 166.93 (—C═O); 158.23; 140.62; 132.14; 129.67; 121.67; 119.53; 114.88; 112.33; 70.95; 19.13.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>[Fe]>[NH2:9][C:5]1[CH:6]=[C:7]([I:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(I)c1
Agent: [Fe]
Product: Nc1cnc(Cl)c(I)c1
Yield: 76.8 %

Procedure:
2-Chloro-3-iodo-5-nitropyridine (0.25g, 0.88 mmol) was reacted with iron powder (0.25g, 4.4 mmol) in the manner described in example 762D. Removal of the solvent in vacuo gave compound 765C (0.172g, 77%), as a golden yellow solid. HPLC: 100% at 2.32 min(YMC S5 ODS column) eluting with 10–90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 255.03 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.[O:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:41][CH:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=CC1CCOCC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC2CCOCC2)C3)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.100 g, 0.252 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) at 0° C. was added tetrahydro-2H-pyran-4-carbaldehyde (0.02752 mL, 0.2522 mmol). The reaction mixture was stirred at 50° C. for 15 minutes then cooled at 0° C. and added Sodium triacetoxyborohydride (0.1069 g, 0.5044 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for 2 hours. LC-MS shows mostly product. The reaction mixture was concentrated, chromatographed through silica gel (40 g, 0-5% MeOH in dichloromethane), and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.15 (d, J=8.7, 2H), 7.46 (d, J=8.7, 2H), 6.16 (t, J=5.5, 1H), 4.13 (d, J=6.7, 1H), 3.85 (t, J=9.0, 3H), 3.70 (d, J=9.0, 1H), 3.61 (dd, J=12.3, 4.0, 4H), 3.52-3.31 (m, 4H), 3.17-3.07 (m, 2H), 2.67 (s, 3H), 2.51 (m, 1H), 2.34 (d, J=7.3, 2H), 1.90 (d, J=7.3, 1H), 1.66 (d, J=12.6, 2H), 1.28-1.10 (m, 5H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.3 (M+H)+.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][NH3+:23])=[O:8])([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:2]([O:6][C:7](=[O:8])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][NH:23][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)Cn1c(SCCC[NH3+])nc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1c(SCCCNC(=O)c2ccccc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-(1-tert-butoxycarbonylmethyl-1H-benzoimidazol-2-ylsulfanyl)-propyl-ammonium chloride (Precursor U-08b, 6 mg, 0.02 mmol) in dichloromethane (0.4 ml) are added subsequently DIPEA (10 mg, 15 μl, 0.085 mmol) and benzoyl chloride (3.9 mg, 3.241l, 0.03 mmol) and the resulting solution is allowed to stir for 1 h at rt. Tris-(2-aminoethyl)amine polystyrene (3.4 mmol/g, 33 mg, 0.11 mmol) is added and the mixture is allowed to stir for another 3 h at rt. The solvent is evaporated and the residue dried under high vacuum, yielding the title compound as a colourless oil: tR=2.62 min (LC-2), ESI-MS (pos.): m/z 510.49 [M+H]+.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[CH:49]1([C:52]([OH:54])=O)[CH2:51][CH2:50]1>>[CH:49]1([C:52]([N:46]2[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][NH:40][C@:5]34[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]3[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4]4)[C@@:19]4([CH3:20])[C@@H:10]([C@:11]5([CH3:33])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[CH2:44][CH2:45]2)=[O:54])[CH2:51][CH2:50]1
Reactant: O=C(O)C1CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (0.9 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using cyclopropanecarboxylic acid as the acylating agent. LCMS: m/e 710.8 (M+H)+, 4.41 min (method 15). 1H NMR (500 MHz, METHANOL-d4) δ 7.88 (d, J=7.9 Hz, 2H), 7.16 (d, J=7.9 Hz, 2H), 5.30 (d, J=4.9 Hz, 1H), 4.78 (s, 1H), 4.67 (s, 1H), 3.84 (br. s., 2H), 3.77-3.50 (m, 2H), 3.09-2.97 (m, 1H), 2.94-2.81 (m, 2H), 2.77 (td, J=10.5, 5.3 Hz, 1H), 2.73-2.57 (m, 4H), 2.48 (br. s., 1H), 2.21-1.82 (m, 8H), 1.75 (s, 3H), 1.73-1.07 (m, 15H), 1.24 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H), 0.93-0.87 (m, 2H), 0.87-0.79 (m, 2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].Cl>C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH3:19])=[CH:13][C:14]([O:17][CH3:18])=[C:15]([C:5](=[O:8])[CH2:6][CH3:7])[CH:16]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(Cl)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1cc(Cl)c(C)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
A suspension of 2.55 g of AlCl3 in 30 ml of DCM is cooled to 0° C. under a nitrogen atmosphere, and a solution of 1.77 g of propionyl chloride in 15 ml of DCM is added dropwise. A solution of 3 g of 2-chloro-5-methoxytoluene in 15 ml of DCM is then added dropwise, and the reaction mixture is left stirring for 2 hours. It is poured into a mixture of concentrated HCl and ice, the organic phase is extracted with DCM and dried over magnesium sulphate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with a DCM/heptane (70:30; v/v) mixture. 2.2 g of the expected product, m.p.=79° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[N:11]1([CH2:17][CH2:18]O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][CH2:17][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12
Reactant: Clc1ncnc2[nH]ncc12
Reactant: OCCN1CCCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1cnn2CCN1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4263.6 %

Procedure:
To a stirred solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.2 g, 1.29 mmol) in anh THF (10 mL), 2-(piperidin-1-yl)ethanol (0.258 mL, 1.94 mmol) and triphenylphosphine (0.51 g, 1.94 mmol) were sequentially added. The reaction mixture was cooled to 0° C. and diisopropylazodicarboxylate (0.38 mL, 1.94 mmol) was added dropwise. The mixture was stirred for 30 min. at 0° C. and kept overnight at 4° C. The solvent was removed at reduced pressure and the residue was dissolved in DCM and washed with diluted HCl 1N. The aqueous phase was separated, basified and extracted with DCM. The organic phase was separated, dried and the solvent was removed under reduced pressure to give a residue that was purified by flash chromatography eluting with (EtOAc/Petroleum ether, 8:2) to yield 4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (146 mg, 55 mmol, 42%) as an oil that solidifies “on standing”.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33](O)=[O:34])=[CH:23][N:22]=1>>[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])=[CH:23][N:22]=1
Reactant: Cc1ncc(C(=O)O)c(-c2ccccc2)n1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1ncc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccccc2)n1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Methyl-4-phenyl-pyrimidine-5-carboxylic acid. LC-MS (basic): tR=1.19 min; [M+H]+=473.1.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[CH:11]=[C:10]([CH:21]([NH:23][OH:24])[CH3:22])[CH:9]=1.[NH4+].[Cl-]>C1COCC1>[OH:24][N:23]([CH:21]([C:10]1[CH:9]=[CH:8][C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[CH:11]=1)[CH3:22])[C:6]([NH2:5])=[O:7]
Reactant: CC(NO)c1ccc2c(c1)oc1ccccc12
Reactant: C[Si](C)(C)N=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(c1ccc2c(c1)oc1ccccc12)N(O)C(N)=O
Yield: 80 %

Procedure:
Trimethylsilyl isocyanate (1.2 mL) was added to a solution of 1-(3-dibenzofuranyl)ethyl hydroxylamine (0.88 g, 3.87 mmole), prepared as described in Example 1, step c, in THF (6 mL). The mixture was heated at 60° for one hour and then poured into saturated NH4Cl solution. This was extracted with ethyl acetate (3×100 mL). The organic layer was concentrated in vacuo and the residue was triturated with ether to give the desired product as a white solid (0.84 g, 80%). (R1=NH2, A=--CH(CH3)--, X=O, Y=H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9]>C(Cl)Cl>[CH3:7][S:8]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCOCC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
To a solution of morpholine (2.00 mL, 22.96 mmol) in DCM (40 mL) was added TEA (3.20 mL, 22.96 mmol) at about −20° C., then methanesulfonyl chloride (2.68 mL, 34.4 mmol) was added dropwise at about −20° C. The reaction mixture was stirred at about −20° C. for about 2 h, then warmed to rt. The mixture was partitioned with saturated aqueous NH4Cl (100 mL) and DCM (3×50 mL). The combined organic layers were concentrated and purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc/heptane to give 4-(methylsulfonyl)morpholine (3.95 g, 100%) as a white solid: 1H NMR (DMSO-d6) δ 3.70-3.60 (m, 4H), 3.12-3.04 (m, 4H), 2.89 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]2[CH:7]=[C:8]([NH2:18])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH2:5][CH2:4]1.N1C=CC=CC=1.[Cl:25][C:26]([Cl:33])([Cl:32])[CH2:27][O:28][C:29](Cl)=[O:30]>C1COCC1>[Cl:25][C:26]([Cl:33])([Cl:32])[CH2:27][O:28][C:29](=[O:30])[NH:18][C:8]1[N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:10]=[C:6]([C:3]2([O:2][CH3:1])[CH2:5][CH2:4]2)[CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COC1(c2cc(N)n(-c3ccc(C)cc3)n2)CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC1(c2cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c3ccc(C)cc3)n2)CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To an ice-salt cooled solution of 5-(1-methoxy-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (Preparation 11, 2.43 g, 10 mmol) and pyridine (0.9 mL, 11 mmol) in THF (30 mL), add a solution of 2,2,2-trichloroethylchloroformate (2.12 g, 10 mmol) in THF (10 mL) dropwise. Stir at −15° C. for 0.5 hour, then at 22° C. for 1 hour. Partition the reaction mixture between dichloromethane (50 mL) and saturated aq. sodium bicarbonate (50 mL). Isolate the aqueous phase and extract twice with dichloromethane (25 mL each). Dry the combined organic phases over sodium sulfate and concentrate. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to give a white solid (3.73 g, 89% yield, ES+(m/z) 418.1 [M+H]).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([N:24]([CH2:27][CH3:28])CC)=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.N[C@H:32]1CC[C@H](C2C=CC(C(N(CC)CC)=O)=CC=2)C[CH2:33]1.C(N)CCC>>[NH2:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:27][CH2:28][CH2:32][CH3:33])=[O:23])=[CH:29][CH:30]=2)[CH2:16][CH2:17]1
Reactant: CCN(CC)C(=O)c1ccc([C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)cc1
Reactant: CCN(CC)C(=O)c1ccc([C@H]2CC[C@H](N)CC2)cc1
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc([C@H]2CC[C@H](N)CC2)cc1

Procedure:
The compound of the title is obtained by carrying out the procedure as described in Preparation 8 (iii) and (iv), but using n-butylamine instead of diethylamine.
Reaction SMILES: [OH:1][CH:2]([CH:16]1[CH2:20][CH2:19][S:18][C:17]1=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.O>O1CCOCC1>[OH:1][CH:2]([CH:16]1[CH2:20][CH2:19][S:18][C:17]1=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)c1ccc(C(O)C2CCSC2=O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc(C(O)C2CCSC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
Ethyl 2-{4-[hydroxy(2-oxothiolan-3-yl)methyl]phenyl}propionate (106 mg) obtained in Example 32 was dissolved in 1,4-dioxane (2.0 ml), and to the solution was added 30% aqueous sulfuric acid (2.0 ml), and the solution was stirred overnight at room temperature. After completion of the reaction, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the title compound (64 mg, 66%).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(OC(=O)C)(=O)C.[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:20]([NH2:22])=[O:21]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:20]([NH:22][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[O:21]
Reactant: N#CCC(=O)O
Reactant: NC(=O)NCc1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)NC(=O)NCc1cccc(Cl)c1
Reaction time: 4 h
Yield: 84.8 %

Procedure:
3.76 g of 98% cyanoacetic acid and 14 ml of acetic anhydride were heated for 1 hour at 65° C. A solution of 7.73 g of (3-chlorobenzyl)urea in 55 ml THF was added and the mixture kept for 4 hours at 65° C. The THF was removed in vacuo and the residue diluted with 50 ml of toluene. The solid was collected and washed to give the title compound (8.94 g) as a white solid.