Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][C@H:6]2[CH2:8][C@H:4]([C:5]2([CH3:10])[CH3:9])[C@@H:3]1[CH2:11][C:12](Cl)=[O:13].[NH2:16][N:17]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:34].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:34])[N:17]([NH:16][C:12](=[O:13])[CH2:11][C@@H:3]3[C:2]([F:15])([F:1])[CH2:7][C@H:6]4[CH2:8][C@@H:4]3[C:5]4([CH3:10])[CH3:9])[N:26]=2)=[CH:28][CH:29]=1
Reactant: CC1(C)[C@@H]2C[C@H]1[C@H](CC(=O)Cl)C(F)(F)C2
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@@H]2C[C@H]1[C@H](CC(=O)Nn1nc(-c3ccc(Cl)cc3)c3ccccc3c1=O)C(F)(F)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of the above crude 2-((1S,2S,5R)-3,3-difluoro-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)acetyl chloride (50 mg, 0.211 mmol) and the product from Example 86A (57.4 mg, 0.211 mmol) in 10 mL of CHCl3 was added pyridine (0.051 mL, 0.634 mmol). The reaction is stirred at rt for 12 hours and then reluxed for 16 hours, and quenched with 1M NaHCO3 (10 mL). The aq layer was extracted with EtOAc (2×20 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-40% of EtOAc in hexanes). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 8.39-8.43 (m, 1H), 7.94-8.00 (m, 2H), 7.70-7.76 (m, 1H), 7.58-7.70 (m, 4H), 2.92-3.09 (m, 1H), 2.81 (dd, J=15.3, 6.4 Hz, 1H), 2.36-2.45 (m, 3H), 2.11-2.16 (m, 1H), 1.93-2.04 (m, 1H), 1.27 (s, 3H), 1.08-1.20 (m, 2H), 1.01 (s, 3H); MS (ESI+) M/Z 472 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[CH2:37][C:38]#[N:39])[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:41]1([CH:44]=O)[CH2:43][CH2:42]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[C:37]([C:38]#[N:39])=[CH:44][CH:41]4[CH2:43][CH2:42]4)[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Reactant: O=CC1CC1
Solvent: C1CCNCC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
Into a 10-mL round-bottom flask, was placed (R)—N-(4-[4-amino-1-[1-(2-cyanoacetyl)piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl)-4-(trifluoromethyl)-benzamide (65 mg, 0.12 mmol, 1.00 equiv), cyclopropanecarbaldehyde (16.6 mg, 0.24 mmol, 2.00 equiv), piperidine (10 mg, 0.12 mmol, 0.99 equiv), methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. The resulting mixture was concentrated under vacuum and the residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50:1) to give 43 mg (60%) of (R)—N-[4-(4-amino-1-[1-[2-cyano-2-(cyclopropylmethylidene)acetyl]piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-4-(trifluoromethyl)benzamide as a white solid. MS (ESI, pos. ion) m/z: 601 (M+1), 1HNMR (300 MHz, CDCl3, ppm), 8.6 (1H, s), 8.348 (1Hs), 8.0658.038 (2H, d, J=8.1), 7.880˜7.852 (1H, d, J=8.4), 7.768˜7.659 (4H, m), 6.532˜6.496 (1H, d, J=10.8), 5.949 (2H, s), 4.976˜4.907 (1H, m), 4.638˜3.218 (4H, m), 2.436˜1.818 (5H, m), 1.221˜1.198 (2H, m), 0.89˜0.772 (2H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].B(O)(O)[C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH2:32])=[CH:27][CH:26]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:25]4[CH:30]=[CH:29][C:28]([CH:31]=[CH2:32])=[CH:27][CH:26]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: C=Cc1ccc(B(O)O)cc1
Product: C=Cc1ccc(-c2nc(-n3cnc4cc(OC)c(OC)cc43)sc2C(=O)O)cc1
Yield: 37.3 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 4-vinylboronic acid (22.2 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(4-vinyl-phenyl)-thiazole-5-carboxylic acid (15.2 mg, 37%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.69 (br.s., 1 H); 8.82 (s, 1 H); 7.95 (d, 2 H); 7.84 (s, 1 H); 7.60 (d, 2H); 7.39 (s, 1H); 6.82 (dd, 1 H); 5.97 (dd, 1 H); 5.37 (dd, 1 H); 3.86 (s, 3 H); 3.86 (s, 3 H). MS 408 m/z (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:17])[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:26]=1[CH2:27]Br.O>CN(C=O)C>[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:26]=1[CH2:27][O:17][C:4]1[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(F)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(F)cn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
560 mg of ethyl 6-fluoro-8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 12A; 2.4 mmol, 1.0 equivalent), 1.7 g of caesium carbonate (5.17 mmol, 2.2 equivalents) and 535 mg of 2,6-difluorobenzyl bromide (2.6 mmol, 1.1 equivalents) were initially charged in 34 ml of dry DMF, and the mixture was heated at 50° C. for 15 min. Water was added and the mixture was stirred for 30 min. The solid was filtered off and washed with water. This gave 560 mg of the title compound (65% of theory).
Reaction SMILES: [CH2:1]([N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[CH:13]=[N:12][C:11]=2[N:10]([CH3:25])[C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CO.[BH4-].[Na+]>C(O)(=O)C>[CH2:1]([N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])[CH:13]=[N:12][C:11]=2[N:10]([CH3:25])[C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c2c(ncn2CCCCC(C)=O)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCn1c(=O)c2c(ncn2CCCCC(C)O)n(C)c1=O

Procedure:
25 g of 1-n-hexyl-3-methyl-7-(5-oxohexyl)-xanthine, 100 ml of methanol and 1.0 g sodium borohydride are stirred at ambient temperature for 30 minutes. The mixture is then acidified with crystalline acetic acid to a pH-value of 5. The alcohol is evaporated and the residue is dissolved in 200 ml of methylene chloride and washed with 2N sodium hydroxide solution and with water. After evaporation of the methylene chloride, the product is recrystallised from 250 ml of diisopropyl ether. The 1-n-hexyl-3-methyl-7-(5-hydroxyhexyl)-xanthine obtained (88% of theory) has a melting point of 68° to 69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)=[O:21])[C:6]([CH2:8]P(=O)(OC)OC)=[O:7].[N:32]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=1.[OH-].[Na+].C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH:8]=[CH:38][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)=[O:21]
Reactant: COc1cc(C(=O)CP(=O)(OC)OC)ccc1OCC(=O)Nc1nc2ccccc2s1
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C(=O)C=Cc2ccncc2)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 5 h
Yield: 79.7 %

Procedure:
To a solution of dimethyl {[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyl}phosphonate (1.7 g) and pyridine-4-aldehyde (0.5 g) in tetrahydrofuran (30 ml) is added a 5% aqueous sodium hydroxide solution (6 ml) under ice-cooling, and the mixture is stirred for 5 hours. The mixture is neutralized with acetic acid, and the precipitated crystals are collected by filtration, and then recrystallized from dichloromethane-ethanol-diethyl ether to give 2-{2-methoxy-4-[3-(4-pyridyl)acryloyl]phenoxymethylcarbonylamino}benzothiazole (1.3 g).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:5][CH2:6][CH3:7])[C:3]#[CH:4].[Na+].[CH3:10][O:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1/[CH:17]=[C:18]1\[C:19](=[O:34])[NH:20][C:21]2[C:26]\1=[C:25](C#CCCC([O-])=O)[CH:24]=[CH:23][CH:22]=2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:8][C:2]([CH3:1])([CH2:5][CH2:6][CH3:7])[C:3]#[C:4][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1/[C:18](=[CH:17]/[C:13]1[NH:14][CH:15]=[CH:16][C:12]=1[O:11][CH3:10])/[C:19](=[O:34])[NH:20]2
Reactant: C#CC(C)(O)CCC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)[O-])c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-hexyn-3-ol (98 mg, 0.87 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material I supra) (127 mg, 0.4 mmol) using (Ph3P)2PdCl2 (46 mg) and CuI (22 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 22 h yielding rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 92 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([C@@H:57]([NH2:66])[CH2:58][O:59][C:60]([O:62][CH:63]([CH3:65])[CH3:64])=[O:61])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:66][C@H:57]([C:55]1[NH:54][C:53]2[CH:67]=[CH:68][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][O:59][C:60]([O:62][CH:63]([CH3:65])[CH3:64])=[O:61])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1
Reactant: CC(C)OC(=O)OC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)OC(=O)OC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 40 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine and (R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-isopropoxycarbonyloxyethylamine in tetrahydrofuran. Yield: 40%; C25H24Cl2N4O5 (531.394); mass spectrum: (M+H)+=531/533/535 (chlorine isotope).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](Cl)=[O:32]>>[F:28][C:29]([F:35])([F:34])[CH2:30][C:31]([N:23]1[CH2:24][CH2:25][C:26]2[N:27]=[C:19]([NH:18][C:8]3[CH:9]=[CH:10][C:11]([N:12]4[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]4)=[C:6]([O:5][CH3:4])[CH:7]=3)[S:20][C:21]=2[CH2:22]1)=[O:32]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Agent: Cl
Product: COc1cc(Nc2nc3c(s2)CN(C(=O)CC(F)(F)F)CC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 45 from 90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 30 mg (0.2 mmol) 3,3,3-trifluoropropionylchloride yielding 29 mg (32%) 3,3,3-trifluoro-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl}-propan-1-one as a light yellow solid. MS ISP (m/e): 452.0 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.33 (s, 1H), 7.65 (S, 1 h), 7.47 (S, 1 h), 7.30-7.25 (m, 2H), 7.02 (s, 1H), 4.57 (br s, 2H), 3.85-3.59 (br m, 2H), 3.78 (s, 3H), 2.75 (m, 1H), 2.62 (m, 1H), 2.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:36]4[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]4)[CH:22]=[CH:23][CH:24]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2cccc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylbenzaldehyde (D74) (120 mg), acetic acid (0.036 mL) and sodium acetate (51.0 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (196 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (165 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-{[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-4-piperidinecarboxylate (D85) (164 mg). The crude product was used for next step without further purification. MS (ES): C29H35ClN2O3S requires 526. found 527.2 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH3:4].C=CCC.[CH:9]([OH:13])([CH2:11][CH3:12])[CH3:10]>O>[CH:2]([O:13][CH:9]([CH2:11][CH3:12])[CH3:10])([CH2:3][CH3:4])[CH3:1]
Reactant: CCCC
Reactant: CCC(C)O
Agent: C=CCC
Solvent: O
Product: CCC(C)OC(C)CC

Procedure:
The procedure described in comparison Example 1 was altered so that by use of an additional dosing pump 54 kgs of the process water (total amount 204 kgs) were charged to the n-butane/n-butene mixture (feedgas and recycle gas=3,000 kgs/h) and transferred to the evaporator. Employing the same conditions as in comparison Example 1 (155° C. to 160° C., 70 bar) a temperature of 155° C. to 162° C. could be maintained in the reactor without additional heating or cooling. In the sump of a column, average amounts of 201.3 kgs (2,720 moles) of sec. butyl alcohol and 2.1 kgs (16.2 moles) of di-sec. butyl ether were obtained per hour as an approx. 99% purity crude alcohol. 101.5 kgs of n-butene and 46.4 kgs of n-butane were obtained as an approx. 59% mixture.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[NH:13][CH2:14][C:15]1[C:16]([NH2:23])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[NH:23][C:1]1=[O:2]
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(N)n1
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Reaction time: 1 h
Yield: 89 %

Procedure:
A stirred solution, cooled in ice, of 5.8 ml (11.2 mmol) of phosgene (20% in toluene) in 80 ml of tetrahydrofuran was treated dropwise with a solution of 1.76 g (5.6 mmol) of 5-(2,6-dichlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidine and 1.6 ml (11.2 mmol) of triethylamine in 80 ml of tetrahydrofuran. The mixture was stirred for 1 hour. 50 ml of tetrahydrofuran and 50 ml of saturated aqueous ammonium chloride solution were added. The phases were separated and the organic phase was washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate, filtered and evaporated to give 1.7 g (89%) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH:12](OC)(OC)OC>>[CH3:11][C:5]1[C:6]2[S:7](=[O:8])(=[O:9])[N:10]=[CH:12][NH:1][C:2]=2[S:3][CH:4]=1
Reactant: Cc1csc(N)c1S(N)(=O)=O
Reactant: COC(OC)OC
Product: Cc1csc2c1S(=O)(=O)N=CN2
Temperature: 90 °C

Procedure:
200 mg of 2-amino-4-methylthiophene-3-sulphonamide, the preparation of which is described in patent WO 99/03861, are dissolved in 1.5 ml of trimethyl orthoformate. The mixture is heated at 90° C. for 2 hours in an open vessel. After evaporation of the solvent under reduced pressure, the residue is taken up in 3 ml of ethyl acetate. The resulting insoluble material is collected by filtration, washed with diethyl ether and dried.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[S:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2)(=[O:15])(=[O:14])[NH2:13].N1CCCCC1>C(O)C>[S:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:1][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)(=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 3-formyl-7-azaindole (1.46 g, 10 mmol), 5-sulfamoyl-2-oxindole (2,122 g, 10 mmol) and piperidine (0,255 g, 3 mmol) in absolute ethanol (50 ml) was treated for 3 h at reflux. The reaction mixture was chilled to room temperature, the precipitate filtered, the residue washed with ice-cold ethanol and dried under vacuum. Almost pure title compound was so obtained in about 70% yield. Compounds of higher purity were obtained by crystallization from ethanol.
Reaction SMILES: Cl.Br.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:14])[C:11]=2[NH2:13])[CH2:6][CH2:5][NH:4]1.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[NH:13]1[C:11]2[C:12]3[CH2:3][NH:4][CH2:5][CH2:6][C:7]=3[CH:8]=[CH:9][C:10]=2[NH:14][C:16](=[O:17])[C:15]1=[O:19]
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2c(c1N)CNCC2
Agent: Br
Agent: Cl
Product: O=c1[nH]c2ccc3c(c2[nH]c1=O)CNCC3
Temperature: 90 °C
Yield: 81.5 %

Procedure:
A solution of Example 29 (01.27 g, 0.96 mmol) in 25 mL 3 N HCl, was treated with oxalic acid (0.15 g, 1.2 mmol) and heated at reflux for 4 h. The mixture was cooled in an ice bath and the precipitate collected by filtration and washed with 3 N HCl, water and then diethyl ether consecutively. After air drying, the solid was suspended in 10 mL water and heated at approximately 90° C., basifyed with ammonium hydroxide solution to pH 8, and filtered hot. The solid was washed first with water, then with diethyl ether and then dried in a vacuum oven to give an off-white solid (0.17 g, 81% yield) mp=294-297° C. MS (CI) M+1, 218; IR 1691, 1659cm−1.
Reaction SMILES: C[O:2][C:3](=[O:19])[C@H:4]([N:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:20].O>O1CCOCC1>[ClH:20].[CH3:18][N:11]([C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]([OH:19])=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)[C@@H](c1ccccc1)N(C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN(c1ccccc1)[C@@H](C(=O)O)c1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
(R)-(Methyl-phenyl-amino)-phenyl-acetic acid methyl ester (I73) (125 mg, 0.49 mmol) is dissolved in dioxane (2 mL). 37% Hydrogen chloride in water (3.00 mL, 36.5 mmol) is added and the mixture is stirred at 70° C. for 18 hours. Then a second portion of 37% hydrogen chloride in water (1.00 mL, 12.2 mmol) is added and the mixture is stirred at 70° C. for additional 36 hours. The mixture is cooled to RT and the white precipitate is filtered and washed with dioxane and Et2O to obtain intermediate I122 as a white solid (97 mg, 71% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.Cl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][N:17]=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1cccs1
Reactant: NNc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(NN=Cc2cccs2)cc1

Procedure:
14.8 g of 2-thiophenecarbaldehyde was added to a mixture of 25.2 g of p-chlorophenylhydrazine hydrochloride and 33.6 g of sodium acetate in 400 ml of 50% aqueous ethyl alcohol. The mixture was heated on a water bath for 30 minutes. After cooling, the precipitated solid was collected and crystallized from ethyl alcohol to give 1, as yellow needles, mp 137° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([O:12]CC=C)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].O1CCCC1.[C:33]([O:37][CH2:38][CH:39]=[CH2:40])(=[O:36])[CH:34]=[CH2:35]>O1CCCC1>[O:12]=[C:10]1[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:35][CH:34]1[C:33]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36]
Reactant: C=CCOC(=O)C=C
Reactant: C=CCOC(=O)CNC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
An ice-cooled (3° C.) stirred solution of N-boc-glycine, allyl ester (6.46 g, 30 mmol) in anhydrous tetrahydrofuran (60 mL) under nitrogen was treated with 1N lithium bis(trimethylsilylamide)/tetrahydrofuran (33 mL, 33 mmol) at a rate to keep pot temperature below 10° C., then stirred at 3° C. for 15 min and cooled (−40° C.). A solution of allyl acrylate (4.45 mL, 35 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise, and the mixture allowed to reach room temperature, stirred 1 h, and refluxed for 2 h. The mixture was cooled to room temperature, quenched with glacial acetic acid (2.5 mL), and concentrated. The residual oil was dissolved in methylene chloride (300 mL) and the solution washed with water and saturated sodium bicarbonate (150 mL each), dried (Na2SO4), and concentrated. The residue was dissolved in minimum methylene chloride and loaded onto a silica gel column (350 mL volume) and eluted with 55:30:15 heptane/methylene chloride/ethyl acetate to afford 3-allyl 1-tert-butyl 4-oxopyrrolidine-1,3-dicarboxylate (5.07 g, 63%) as a colorless oil. NMR (CDCl3): δ 5.85-6.00 (m, 1 H), 5.20-5.40 (m, 2 H), 4.60-4.75 (m, 2 H), 4.20 (m, 1 H), 3.95-4.10 (m, 1 H), 3.87 (d J=6.5 Hz, 1 H), 3.62 (t, J=8 Hz, 1 H), 1.48 (s, 9 H). MS (m+1): 270.4; MS (m−bu+1): 214.2.