Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:9][C:8]=2[CH:18]=1)([O-])=O>[Pd].CCOC(C)=O.CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[N:9][C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2oc(CN3CCCC3)nc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2oc(CN3CCCC3)nc2c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-nitro-2-[(pyrrolidin-1-yl)methyl]benzoxazole (300 mg, 1.21 mmol) in a mixed solvent of EtOAc-MeOH (1:1, 70 mL) was added 10% Pd—C (40 mg), the flask was purged with argon, then the argon was replaced with H2, the reaction mixture was stirred under H2 atmosphere for 30 min. After filtration through Celite, washed with ethyl acetate. The solvents were evaporated to provide 263 mg (100%) of 5-amino-2-[(pyrrolidin-1-yl)methyl]benzoxazole as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH:12]([Br:17])[CH:13]3O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>CCOCC>[C:1]1([C:7]2[CH:15]=[C:14]3[C:10](=[CH:9][CH:8]=2)[CH2:11][C:12]([Br:17])=[CH:13]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1c2cc(-c3ccccc3)ccc2CC1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: BrC1=Cc2cc(-c3ccccc3)ccc2C1
Yield: 79.3 %

Procedure:
To a one-necked flask of 500 ml, fitted with an dropping funnel and on top of the funnel a condenser, was added 10.19 g (35.2 mmol) of 6-phenyl-2-bromoindanol, 0.671 g (0.10 mol %) p-toluenesulfonic acid and 350 ml of toluene. After 7 hours of refluxing the mixture was diluted with ether and extracted with water and water/NaHCO3. The organic layer was dried over Na2SO4. The Na2SO4 was filtered off and the filtrate was evaporated under reduced pressure. The solid material was dissolved in hot n-pentane and recrystallized giving 7.56 g (27.9 mmol) of 5-phenyl-2-bromoindene. Yield 79%.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=O)=[C:9]([C:21]#[N:22])[C:8]([CH2:23][CH3:24])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:25](C)[Na].OO>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:22][C:21](=[O:25])[C:9]3=[C:8]([CH2:23][CH3:24])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c(NC(=O)Cc2ccncc2)c1C#N
Reactant: CO[Na]
Agent: OO
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-4-cyano-5-[(4-pyridinylmethyl)carbonylamino]-1H-pyrazole (2.8 g, 8.6 mmol), ethanol (50 ml), NaOCH3 (1.0 g, 18 mmol) and 30% H2O2 (4.5 ml) was stirred at room temperature for 20 minutes, then was heated at reflux for 3.5 hours. Additional 30% H2O2 (3 ml) was added and the reaction mixture was heated at reflux for 2 more hours. The reaction mixture was concentrated in vacuo, the residue was partitioned between CHCl3 (100 ml) and 10% aqueous NaHCO (50 ml), and the organic layer was separated. The organic layer was concentrated in vacuo, and the residue was crystallized from cyclohexane and a solid was collected by filtration. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ether to 10% methanol/ether, followed by recrystallization from ether, to afford 420 mg of 1-cyclopentyl-3-ethyl-6-(4-pyridinylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 162°-164° C.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@@H:17]([CH2:28][OH:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:29][CH2:28][C@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: C[C@]12CCCCC1[C@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1[C@H](CO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
The title compound (II-ai) was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-6β-hydroxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.71-3.47 (m, 3H), 2.82-0.79 (m, 21H), 1.08 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23](Cl)[N:22]=1)([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:23]2[N:22]=[C:21]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(C)(C)Nc1nc(Cl)nc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)Nc1nc(NC2CCC(NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Temperature: 170 °C
Yield: 64.5 %

Procedure:
To a suspension of cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (122 mg, 0.57 mmol) in 2-propanol (2 mL) were added tert-butyl-(2-chloro-quinazolin-4-yl)-amine (100 mg, 0.42 mmol) and diisopropylethylamine (180 μL, 1 mmol) and the mixture was heated at 170° C. for 1 hr using a Smith Microwave Synthesizer. The resulting solution was concentrated and purified by column chromatography (silica gel, 3% MeOH in CH2Cl2) to give [4-(4-tert-butylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (112 mg, 65%) as a yellow solid. To a suspension of cis-[4-(4-tert-butylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (95 mg, 0.23 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (2 mL) dropwise. The reaction mixture was stirred at ambient temperature for 2 hr. The solution was concentrated, alkalized with saturated aqueous NaHCO3 and 1 M aqueous sodium hydroxide (pH=9), and the aqueous layer was extracted with CH2Cl2 (three times). The combined organic layer was dried over MgSO4, filtered, and concentrated. The solid was collected by filtration to give cis-N2-(4-amino-cyclohexyl)-N-tert-butyl-quinazoline-2,4-diamine (44.6 mg, 53%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[CH2:24])=[CH:17][CH:16]=2)[C@H:10]([O:25][CH2:26][C@H:27]2[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:35][C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]2[C:44]([CH:45]=1)=[CH:43][CH:42]=[CH:41][CH:40]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:35][C:36]2[CH:37]=[C:38]([O:46][CH3:47])[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:45]=2)[C@@H:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]=[CH2:24])=[CH:19][CH:20]=2)[C@H:10]([O:25][CH2:26][C@H:27]2[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(CCl)cc2ccccc12
Reactant: C=CCOc1ccc([C@@H]2[C@@H](O)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2COC(C)(C)O2)cc1
Product: C=CCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2COC(C)(C)O2)cc1

Procedure:
In analogy to the procedure described in example 1) (f) the (3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was reacted with 3-chloromethyl-1-methoxy-naphthalene [example 1) (α)] to yield the (3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 634(M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:12][NH2:13]>>[C:1]1([S:7]([NH:12][NH2:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Product: NNS(=O)(=O)c1ccccc1

Procedure:
Benzenesulfonohydrazide is prepared from benzenesulfonyl chloride (500 mg, 2.83 mmol) and hydrazine monohydrate (0.42 mL, 8.49 mmol) according to the experimental provided in Tetrahedron 2002, 58, 5513. The product is recrystallized from EtOAc/Hexane. The yield is 136 mg of benzenesulfonohydrazide, 28%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:40][CH2:39][C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)(=[O:24])=[O:25]
Reactant: NCc1cccnc1
Reactant: Cc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)c1
Yield: 39.8 %

Procedure:
Method E. Reaction of oxalyl chloride (56 λL, 0.64 mmol) and benzoic acid 32 (158 mg, 0.43 mmol) with subsequent coupling to 3-pyridinylmethylamine (48 λL, 0.47 mmol) gave benzamide 33 (79 mg, 40%) as a white powder: mp (EtOAc) 179-181° C.; 1H NMR δ 9.20 (t, J=5.8Hz, 1 H, CONH), 8.57 (d, J=1.8Hz, 1 H, H-2′), 8.47 (dd, J=4.7, 1.6Hz, 1 H, H-6′), 8.00 (d, J=8.5Hz, 2 H, H-2, H-6), 7.90 (br d, J=8.5Hz, 2 H, H-3, H-5), 7.74 (dt, J=7.9, 1.9Hz, 1 H, H-4′), 7.63 (br s, 1 H, H, H-2″) 7.53-7.60 (m, 2 H, H-4″, H-6″), 7.50 (t, J=7.6Hz, 1 H, H-5″), 7.36 (ddd, J=7.9, 4.7, 0.5Hz, 1 H, H-5′), 4.65 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 2.37 (s, 3 H, CH3), 2.16 (s, 3 H, CH3); 13C NMR δ 165.4, 157.9, 149.9, 148.8, 148.0, 139.0, 138.3, 135.3, 135.1, 134.8, 134.3, 128.9, 128.7, 128.3, 128.0 (2), 125.8, 125.3 (2), 125.2, 123.3, 52.8, 40.4, 20.6, 9.67; MS m/z 462.8 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 64.06, 5.02; N, 9.10. Found: C, 64.76; H, 5.06; N, 9.05%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][N:8]([CH3:18])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:3][CH2:2]1.[C:19]1([C:25]2[O:26][C:27]([C:33]([F:36])([F:35])[F:34])=[C:28]([C:30](O)=[O:31])[N:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][N:8]([CH3:18])[C:9]2[N:10]=[CH:11][C:12]([NH:15][C:30]([C:28]3[N:29]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:26][C:27]=3[C:33]([F:35])([F:36])[F:34])=[O:31])=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: CN(CCOCC1CC1)c1ccc([N+](=O)[O-])cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCOCC1CC1)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 63.3 %

Procedure:
(2-Cyclopropylmethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (82 mg, 0.326 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (92 mg, 0.359 mmol), Et3N (229 uL, 1.63 mmol) and BOP (151 mg. 0.326 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide as a solid (95 mg). ES-MS calcd for C23H23F3N4O3 (m/e) 460.46, obsd 461.1 (M+H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:53]2[CH:54]=[C:55]3[CH:61]=[CH:60][N:59]([CH3:62])[C:56]3=[N:57][CH:58]=2)[C:16]([C:18]2[CH:19]=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=3[C:34]([N:36]3[C@H:45]([CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37]3)=[O:35])[N:21]3[C:26]=2[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:83][C:84]([N:86]1[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1)=[O:85].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:53]2[CH:54]=[C:55]3[CH:61]=[CH:60][N:59]([CH3:62])[C:56]3=[N:57][CH:58]=2)[C:16]([C:18]2[CH:19]=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:83][C:84](=[O:85])[N:86]4[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]4)=[CH:29][C:28]=3[C:34]([N:36]3[C@H:45]([CH2:46][N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37]3)=[O:35])[N:21]3[C:26]=2[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(O)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Reactant: O=C(CO)N1CCCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(OCC(=O)N5CCCCC5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
The compound of Step D (3.0 g, 2.9 mmol) is dissolved in 100 mL of toluene. 1.53 g (5.8 mmol) of triphenylphosphine and 0.62 g (4.3 mmol) of 2-hydroxy-1-(1-piperidyl)ethanone are added thereto. The mixture is heated to 50° C., and then 1.01 g (4.3 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is stirred at 50° C. for 1 hour and is then allowed to return to ambient temperature before adding 1 mL of trifluoroacetic acid. After stirring overnight at ambient temperature, the mixture is successively washed with water, saturated NaHCO3 and brine solution. The combined aqueous phases are extracted with ethyl acetate. The resulting organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product obtained is purified by chromatography over silica gel (dichloromethane/ethanol 98/2) to yield the expected compound.
Reaction SMILES: BrC1C(N[C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26]([OH:28])=[O:27])=[O:19])=CC2N(C=C(C3C=CC=CC=3)N=2)C=1.[N:29]1([C:35]2[N:40]3[CH:41]=[C:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:43]=[C:39]3[CH:38]=[C:37]([NH2:50])[N:36]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:25][N:24]1[C:20]([C:18](=[O:19])[NH:50][C:37]2[N:36]=[C:35]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:40]3[CH:41]=[C:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:43]=[C:39]3[CH:38]=2)=[C:21]([C:26]([OH:28])=[O:27])[CH:22]=[N:23]1
Reactant: Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1

Procedure:
The title compound was prepared in analogy to 5-(6-bromo-2-phenyl-imidazo[1,2-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (Example 67, Step 4-6), using 5-morpholin-4-yl-2-phenyl-imidazo[1,2-c]pyrimidin-7-ylamine (as prepared in Example 63, Step 1) in Step 4. MS (m/e)=448.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](#[N:13])[CH:11]=[CH2:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:12][CH2:11][C:10]#[N:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C=CC#N
Product: COc1ccc(OCCC#N)cc1

Procedure:
A mixture of 4-methoxyphenol (10 g: 80.5 mmol) and Triton B (2.29 ml:14.5 mmol:0.18 eq.) in acrylonitrile (50 ml) is heated at reflux for 48 hours. After the solvent has been partially removed, the products are extracted with ethyl acetate and washed with water and then with a 6N hydrochloric acid solution. The residual chestnut-brown oil is purified on a flash silica column eluted with an AcOEt/PE gradient.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[N:22]C(OCC)=O)=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[NH:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH:30]([CH2:31][OH:32])[CH2:33][OH:34]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC(CO)CO)c3cc2Br)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=N)(=O)c1cccc(COc2cc3ncnc(NC(CO)CO)c3cc2Br)c1
Yield: 24 %

Procedure:
According to GWP 6, the conversion of (RS)-S-(3-{[(6-bromo-4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}quinazolin-7-yl)oxy]methyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide (45 mg, 0.081 mmol) and preparation thin layer chromatography (silica gel, dichloromethane/methanol: 4/1) gives the desired product in 24% yield (9 mg).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]([NH:29][O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])[CH2:15]1)(=[O:13])=[O:12]>CC(O)=O>[C:1]([NH:8][CH2:9][CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]([NH:29][O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])[CH2:15]1)(=[O:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)ONC(=O)[C@H]1CN(S(=O)(=O)CCN)CCN1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: CC(=O)NCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NOC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Acetic anhydride (36 mg) was added to a solution of (2R)-4-(2-aminoethanesulfonyl)-N-tert-butoxy-1-tert-butoxycarbonyl-2-piperazinecarboxamide (130 mg) in AcOH (2 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and saturated aqueous NaHCO3 solution. The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo to give 142 mg of (2R)-4-[2-(acetylamino)-ethanesulfonyl]-N-tert-butoxy-1-tert-butoxycarbonyl-2-piperazinecarboxamide.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:28]3[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.13) (0.31 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as a white solid (0.093 g, 29%). MS (ISP) 398.0 [(M+H)+]; mp 267-269° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[C:8]#[CH:9]>ClCCl.CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1]/[CH:9]=[CH:8]/[C:7]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C#CC(=O)OCC
Reactant: Nc1nccs1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)/C=C/Nc1nccs1
Yield: 51 %

Procedure:
A solution of 2.3 g of 2-aminothiazole and 1.55 ml of ethyl propiolate in 10 ml of dichloromethane and 5 ml of dimethylformamide was stirred at ambient temperature for 3 days. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using first 20% then 40% ethyl acetate in hexane to provide 1.54 g (51%) of the desired compound. 1H NMR (CDCl3) δ1.30 (t, J=7 Hz, 3H), 4.22 (q, J=7 Hz, 2H), 5.79 (d, J=15 Hz, 1H), 6.03 (d, J=5 Hz, 1H), 6.68 (d, J=5 Hz, 1H), 7.47 (br, 1H), 8.17 (d, J=15 Hz, 1H). Mass spectrum: (M+H)+ =199.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11](Br)=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[Cu][C:17]#[N:18].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([C:17]#[N:18])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Reactant: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution of 4-bromoisophthalic acid dimethyl ester 202 (2.95 g, 10.8 mmol) in anhydrous DMF (50 ml), Copper(I) cyanide (1.20 g, 13.5 mmol) was added in one portion. The slurry solution was heated at reflux temperature for one hour. When the solution was cooled to ambient temperature, it was poured into 300 mL of ammonium chloride solution (10%) at 0° C. White precipitate was formed. The slurry solution was stirred at ambient temperature for 30 minutes. Then it was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate. Removal of solvent gave white solid which was washed with cold methanol to give 1.89 g (80%) of 4-cyanoisophthalic acid dimethyl ester 203: 1H NMR (400 MHz, CDCl3) δ 3.95 (s, 3H), 4.05 (s, 3H), 7.91 (d, J=8 Hz, 1H), 8.30 (dd, J=1.7 Hz, J=8 Hz, 1H), 8.77 (d, J=1.7 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH-].[Na+].CCOCC>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:3]2[CH:2]([CH3:1])[CH2:6][N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]=2)=[CH:18][CH:17]=1
Reactant: CC1CN(c2ccccc2)N=C1O
Reactant: COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(NC2=NN(c3ccccc3)CC2C)cc1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A 100 ml round bottom flask was charged with 4-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-ol (1.00 g, 5.68 mmol), 4-methoxybenzenamine (2.27 g, 18.44 mmol), and p-toluenesulfonic acid monohydrate (0.59 g, 3.12 mmol). The reaction mixture was stirred at 140° C. under a nitrogen atmosphere for 16 h. The reaction was cooled and dissolved in 1% NaOH solution and ether. The organic layer was separated, washed with 1% HCl solution and water, then dried over Na2SO4, filtered, and concentrated to afford N-(4-methoxyphenyl)-4-methyl-1-phenyl-4,5-dihydro-1-H-pyrazol-3-amine as a brown solid. MS m/z=282.2 [M+H]+. Calc'd for C17H19N3O: 281.35.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C(C)=O)cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 82 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound.