Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[F:2][C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].[CH3:9][C:10]([CH3:55])([CH3:54])[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[C:32](=[O:33])[N:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:30]=[CH:29][C:28]=3[N:41]3[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:12]>ClCCl>[F:2][C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[C:32](=[O:33])[N:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)[N:30]=[CH:29][C:28]=3[N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)(=[O:12])[C:10]([CH3:55])([CH3:54])[CH3:9]
Reactant: Cc1ccc(-n2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccc(-c4ccc(OC(=O)C(C)(C)C)cc4)cc3)c2=O)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2ncc(N3CCNCC3)c(Oc3ccc(-c4ccc(OC(=O)C(C)(C)C)cc4)cc3)c2=O)cc1
Reaction time: 0.75 h

Procedure:
0.2 ml of water and 2.2 ml of trifluoroacetic acid are added dropwise to a solution of 568 mg (0.889 mmol) of the compound from Example 2 in 4.5 ml of dichloromethane at room temperature. After 45 min, the reaction mixture is concentrated and thoroughly dried under high vacuum.
Reaction SMILES: [CH:1]1([C@H:7]([NH:31]C(=O)OC(C)(C)C)[C:8](=[O:30])[NH:9][C:10]2[CH:11]=[C:12]3[C:28](=[O:29])[NH:27][N:26]=[CH:25][C:14]4=[C:15]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[NH:16][C:17]([CH:18]=2)=[C:13]34)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].C(Cl)Cl>CO.C(OCC)C>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[NH2:31][C@@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]([NH:9][C:10]1[CH:11]=[C:12]2[C:28](=[O:29])[NH:27][N:26]=[CH:25][C:14]3=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][C:17]([CH:18]=1)=[C:13]23)=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C1CCCCC1
Yield: 24 %

Procedure:
Preparation of example 34 from the title compound of Example 33 (40 mg, 0.078 mmol), and 1:1 TFA/CH2Cl2 (5 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, included a further trituration with methanol/diethyl ether and afforded the title compound (10 mg, 0.019 mmol) as an orange/yellow powder in 24% yield.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:34])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:14])[CH:11]=2)[S:6][CH2:5][CH2:4]1.C([Li])CCC.[CH3:40][N:41]([CH3:53])[CH2:42][CH2:43][O:44][C:45]1[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=1>O1CCCC1>[CH3:34][C:3]1([CH3:2])[C:12]2[CH:11]=[C:10](/[C:13](/[CH3:14])=[CH:49]/[C:48]3[CH:51]=[CH:52][C:45]([O:44][CH2:43][CH2:42][N:41]([CH3:40])[CH3:53])=[CH:46][CH:47]=3)[CH:9]=[CH:8][C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: CN(C)CCOc1ccc(C=O)cc1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCS2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(OCCN(C)C)cc1)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 44.1 %

Procedure:
32 g of [1-(4,4-dimethyl-6-thiochromanyl)ethyl]triphenylphosphonium bromide were suspended in 130 ml of tetrahydrofuran and treated at 0° C. with 37 ml of n-butyllithium (1.6 molar in hexane). After stirring at 0° C. for 45 minutes, a solution of 10 g of 4-(2-dimethylaminoethoxy)benzaldehyde in 60 ml of tetrahydrofuran was added dropwise to the orange reaction mixture. The mixture was stirred at room temperature for an additional 1 hour, poured on to ice/water and extracted with ether. The organic phases were washed with water, dried and evaporated. After filtration of the crude product over neutral Alox (eluting agent ether) and recrystallization from hexane/ether, there were obtained 8.7 g of 2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)propenyl]phenoxy]-N,N-dimethylethylamine, melting point 81°-82° C.
Reaction SMILES: N=NC=NN.C(=O)([O-])[O-].[K+].[K+].[CH:12](=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([O:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[CH:12]=[O:20])[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: O=Cc1ccccc1O
Agent: N=NC=NN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccccc1C=O

Procedure:
Synthesis of formazan monomer used copolymers E34, E35, E36, E37 of table 1, infra. ##STR6## Potassium carbonate (24.0 g, 173.9 mmol) was added to an ethanolic solution containing salicylaldehyde (19.0 g, 155.7 mmol) an allyl bromide (22.0 g, 181.8 mmol). The resulting suspension was heated to reflux overnight. The precipitated inorganic salt was filtered off. The filtrate was evaporated under reduced pressure to give the desired product, 2-allyloxy-benzaldehyde.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([C@@H:34]([NH2:38])[CH2:35][O:36][CH3:37])[NH:31][C:30]=2[CH:39]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.ClCCl>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([C@@H:34]([NH:38][C:2]3[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=[C:6]([N:8]4[CH2:9][CH2:10][N:11]([C:14]5[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=5)[CH2:12][CH2:13]4)[N:7]=3)[CH2:35][O:36][CH3:37])[NH:31][C:30]=2[CH:39]=1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Reactant: COC[C@H](N)c1nc2ccc(Cl)cc2[nH]1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2)c1nc2ccc(Cl)cc2[nH]1
Temperature: 120 °C
Yield: 37.8 %

Procedure:
200 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 235 mg (R)-1-(6-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine and 179.62 μl diisopropylethylamine are placed in 4 ml dioxane, and the mixture is heated to 120° C. in the microwave for 0.3 hours. Then the reaction mixture is combined with water and dichloromethane and extracted. The product is purified by semipreparative HPLC (method A). 113 mg of the product are obtained as a powder. Analytical HPLC-MS, (method B): RT=1.88 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.CS(Cl)(=O)=O.Cl.P([O-])([O-])(O)=O.[Na+].[Na+].[CH2:23]([N:25](CC)CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:23]#[N:25])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: OCc1ccc(Cl)nc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=P([O-])([O-])O
Solvent: ClCCl
Product: N#CCc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of (6-chloropyridin-3-yl)methanol from Step 1 (7.5 g) and triethylamine (8.7 mL) in dichloromethane (250 mL) was slowly added methanesulphonyl chloride (4.5 mL). The reaction mixture was stirred at 0° C. for 1 hour. Then poured into ice and HCl (1N), adjusted pH at 4 with saturated aqueous disodium hydrogen phosphate and partitioned. The aqueous layer was extracted with dichloromethane (1×150 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was dissolved in DMF (100 mL) and sodium cyanide (2.8 g) was added. The reaction mixture was stirred at room temperature for 3 hours and poured into ice and water (100 mL). Extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:5 to 1:2) to yield the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:43]=[CH:42][C:28]([O:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[CH:14]1([C:12]([NH:11][C:9]2[CH:10]=[C:3]3[C:2]([C:25]4[CH:43]=[CH:42][C:28]([O:29][C@@H:30]5[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:31]5)=[CH:27][CH:26]=4)=[CH:7][CH:6]=[CH:5][N:4]3[N:8]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Reactant: O=C(Nc1cc2c(Br)cccn2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(-c3cccn4nc(NC(=O)C5CC5)cc34)cc2)C1
Temperature: 25 °C

Procedure:
N-(4-Bromopyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (265 mg, 0.95 mmol), (R)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate (442 mg, 1.14 mmol), PdCl2dppf (39 mg, 0.047 mmol) and Na2CO3 (501 mg, 4.73 mmol) were stirred in 1,4-dioxane (15 ml) and water (3 ml) and heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and filtered through celite. The residue was partitioned between EtOAc and water and the aqueous phase was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give (R)-tert-Butyl 3-(4-(2-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyridin-4-yl)phenoxy)pyrrolidine-1-carboxylate as a brown oil which was used in the next step without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35](=[O:41])[NH:36][C@H:37]([CH3:40])[CH2:38]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl.O>[CH2:27]([O:34][C:35](=[O:41])[NH:36][C@H:37]([CH3:40])[CH2:38][I:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: C[C@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@H](CI)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5 g, 184 mmol) in CH2Cl2 (231 ml), then was cooled to 0 degrees C. Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reaction mixture turned yellow, then faintly brown. After 5 minutes ((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid benzyl ester (9.59 g, 45.9 mmol) was added and the reaction mixture was warmed to RT then stirred for 3 h. Then, H2O (7 ml) was added and the reaction mixture was partitioned between CH2Cl2 (300 ml) and H2O (600 ml). The aqueous layer was extracted again with CH2Cl2 (200 ml). The combined organic layer was then washed with a solution of 1:9 aq. saturated Na2S2O3: H2O (140 ml), then brine (400 ml). The combined organics were dried with MgSO4, filtered, concentrated in vacuo, then filtered through a plug of silica gel washing with 15% EtOAc/hexanes (1.5 liter). The solution was concentrated in vacuo, then the solid was washed with hexane and the resultant white solid was used in the next reaction without further purification (11 g, 75%).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)([O-])=O.[NH:13]1[C:21]2C(=CC=CC=2)C(CN[C@@H](CCC2NC=C(C3C=CC=CC=3)N=2)C(OCC2C=CC=CC=2)=O)=[CH:14]1.C(N(CC)CC)C>C1COCC1>[N:10]([CH2:7][CH2:8][CH2:9][CH2:4][CH2:5][CH2:6][N:13]([CH3:21])[CH3:14])=[C:11]=[S:12]
Reactant: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1c[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCCCCCN=C=S
Temperature: 20 °C
Reaction time: 2 h
Yield: 241.3 %

Procedure:
4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (93 mg; 1 eq.) in THF (2 ml). The mixture is stirred for 2 hours at approximately 20° C. then diluted with 4 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine). Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound (90 mg; 84% yield).
Reaction SMILES: [F:1][C:2]([F:19])([CH:16]([F:18])[F:17])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1C)S([O-])(=O)=O.[OH:20][C:21]1C=C(C=CC=1)C=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:19][C:2]([F:1])([CH:16]([F:17])[F:18])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:21]=[O:20]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1OCC(F)(F)C(F)F
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC(F)(F)C(F)F)c1
Temperature: 92 °C
Reaction time: 22 h

Procedure:
Combine 3-(2,2,3,3-tetrafluoropropoxy)tosylate (200 g, 0.664 mol), 3-hydroxybenzaldehyde (101.7 g, 0.833 mol), dimethylformamide (1.5 L) and powdered potassium carbonate (192 g). Heat under stirring at 92° C. for about 22 h. Cool the reaction mixture to 40° C., pour over ice-water and extract with ethyl acetate. Combine organic phases, wash with 1 N sodium hydroxide (1 L and 0.5 L) and then a solution of saturated sodium hydrogen carbonate, dry over magnesium sulfate, filter, evaporate to dryness to provide a oily residue. Distill the oily residue under reduced pressure in a Claisen flask to give a first fraction of the title compound: bp 108-110° C. under 0.4-0.5 mmHg and a second fraction at 110-111° C. under 0.4-0.5 mmHg.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[N:15]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]34[CH2:32][CH:31]3[CH2:30][NH:29][CH2:28]4)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.[CH3:42][O:43][CH2:44][CH2:45]Cl>CN(C=O)C>[CH3:42][O:43][CH2:44][CH2:45][N:29]1[CH2:30][CH:31]2[C:27]([C:24]3[CH:23]=[CH:22][C:21]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:26][CH:25]=3)([CH2:32]2)[CH2:28]1
Reactant: COCCCl
Reactant: c1cc(C23CNCC2C3)ccc1N1CCOCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CC2CC2(c2ccc(N3CCOCC3)cc2)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
To a solution of dihydrochloride salt of 1-(4-morpholin-4-yl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Example XXI) (250 mg, 0.89 mmol) in anhydrous DMF (5 mL) were added DIPEA (0.63 mL, 3.56 mmol) and 2-methoxyethyl chloride (0.12 mL, 1.3 mmol) at r.t. and reaction mixture was stirred at 100° C. for 16 h. Progress of the reaction was monitored by TLC. On completion, reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 0.25:9.75 MeOH:CHCl3) to afford the title compound as viscous liquid (100 mg, 37%).
Reaction SMILES: [C:1]1([C:11](=[O:13])[CH3:12])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[C:1]1([CH:11]([OH:13])[CH3:12])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2cccccc1-2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(O)c1ccc2cccccc1-2

Procedure:
1-(Azulen-1-yl)ethanone (13.0 g) prepared according to a method described in the literature (Mori et al., J. Heterocycl. Chem., Vol. 33, 1996, pp. 841-846) was dissolved in dehydrated THF (380 mL), and stirried with cooling on ice under nitrogen atmosphere. This reaction mixture was carefully added with lithium aluminum hydride (1.45 g, Wako Pure Chemical Industries), and stirried with cooling on ice for 1 hour. The reaction mixture was carefully added with 2 N aqueous sodium hydroxide with cooling on ice and stirring. The reaction mixture was added with anhydrous magnesium sulfate, and stirred, then the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was used for the subsequent reaction as it was.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+].O>CO>[Br:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([C@@H:4]2[CH2:5][C@H:3]2[NH:2][CH2:5][CH2:3][CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:7][CH:8]=1)=[O:21]
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Br)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: CCCCCCCCN[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Br)c2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-bromobenzamide hydrochloride (80 mg) in methanol (2 mL) were added octylaldehyde (34 μL) and sodium hydrogen carbonate (27.4 mg). The reaction mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (12.4 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized (hexane/ethyl acetate) to give the title compound (48.3 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[N:14]=[N:15][C:16]([CH2:21][OH:22])=[CH:17][C:18]=1[O:19][CH3:20].C(N(CC)CC)C>ClCCl.O>[CH3:20][O:19][C:18]1[CH:17]=[C:16]([CH:21]=[O:22])[N:15]=[N:14][C:13]=1[O:12][CH3:11]
Reactant: COc1cc(CO)nnc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(C=O)nnc1OC
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
A solution of oxalyl chloride (0.61 mL) in dichloromethane (11 mL) is cooled to −60° C. and dimethylsulphoxide (0.98 g) is added dropwise maintaining the reaction mixture at −60° C. After 15 minutes a solution of 3,4-dimethoxy-6-hydroxymethylpyridazine (1.0 g) in dichloromethane (42 mL) is added dropwise during 45 minutes maintaining the reaction mixture at −60° C. After a further 15 minutes triethylamine (3.96 mL) is added, the mixture stirred at −60° C. for 15 minutes then cooling is discontinued. When the reaction mixture attains room temperature stirring is continued for 1 hour. The reaction mixture is diluted with water (100 mL) and dichloromethane (100 mL) and the organic phase separated. The aqueous phase is re-extracted with dichloromethane (100 mL) and the combined extracts are dried (MgSO4). Evaporation gave 5,6-dimethoxypyridazine-3-carboxaldehyde (0.95 g) as a white solid, m.p. 179–81° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].Cl[CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>CN1CCCC1=O>[CH2:20]([C:7]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[CH2:25][CH2:26][CH2:27][S:28]2(=[O:30])=[O:29])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN1CCCS1(=O)=O
Yield: 11.3 %

Procedure:
Using the general method of Example 266 except that 1-methyl-2-pyrrolidinone was used in place of dichloromethane, 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (5.0 g, 16.0 mmol) was reacted with 3-chloropropanesulfonyl chloride (2.83 g, 16.0 mmol) to provide 0.75 g of 2-butyl-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 173.0–176.0° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].C[N:18](C)C=O>>[NH2:18][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: NC(=O)c1ccnc(Cl)n1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccnc(N)n1

Procedure:
The amine of formula (V) is thus obtained, and this is reacted with 2-chloropyrimidine-4-carboxamide of formula (VI) in an aprotic solvent, for example dimethylformamide, in the presence of a base, for example potassium carbonate, at a temperature of 20° to 80° C., especially 20° C. to 40° C., to give a 2-aminopyrimidine-4-carboxamide derivative of formula (I). The compound of formula (I) is, if desired, converted into an acid addition salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]#[C:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]#[C:23][CH2:24][CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CCC#CCBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCC#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g) is alkylated using 1-bromo-2-pentyne (3.1 ml; 30.4 mmol) and K2CO3 (4.2 g; 30.4 mmol) at 40° C. for 20 h. After aqueous work-up only a part of the crude material (1 g; 3.04 mmol) is de-acetylated under reflux using DBU (0.9 ml) in MeOH (80 ml). After aqueous work-up the crude 5-amino-3,3-dimethyl-6-nitro-1-(pent-2-ynyl)-1,3-dihydro-indol-2-one (0.87 g) is used without further purification.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[CH:14]=[C:15]([CH3:18])[CH:16]=O)C.C[O-].[Na+].O>CO>[CH3:18][C:15]1[CH:14]=[N:9][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:10][CH:16]=1
Reactant: CCOC=C(C)C=O
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cnc(-c2ccccc2)nc1
Reaction time: 0.5 h

Procedure:
To a solution of benzamidine hydrochloride (500 mg, 3.19 mmol) and 3-ethoxy-2-methylacrylaldehyde (400 mg, 3.51 mmol) in Methanol (10 mL) was added a NaOMe-solution (30 percent in methanol) dropwise under stirring over 30 minutes. After stirring for 4 hours water (20 mL) was added and mixture was stirred for further 30 minutes at room temperature. After filtration the obtained precipitate was washed with water and dried. White solid. Yield: 220 mg, 41%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.34 (s, 3H), 7.44-7.54 (m, 3H), 8.37-8.45 (m, 2H), 8.64 (d, J=0.6 Hz, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=15.7, 128.1, 128.5, 128.8, 130.6, 137.9, 157.6, 162.7; (ESI): m/z=170.97 [M+H]+.
Reaction SMILES: [CH2:1]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)[CH3:2].[C:8]([C-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)#[CH:9].[Fe+2:15].[I:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1>C1COCC1.CCN(CC)CC.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>[CH2:1]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)[CH3:2].[I:16][C:17]1[CH:22]=[CH:21][C:20]([C:9]#[C:8][C-:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)=[CH:19][CH:18]=1.[Fe+2:15]
Reactant: Ic1ccc(I)cc1
Reactant: C#C[c-]1cccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Ic1ccc(C#C[c-]2cccc2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
Following the procedure for preparing 6, samples of 13 (1.0 g, 4.2 mmol), 1,4-diiodobenzene (2.8 g, 8.5 mmol), PdCl2(PPh3)2 (30 mg, 43 μmol) and CuI (5.0 mg, 26 μmol) were reacted in THF (20 mL) and Et3N (20 mL). The reaction mixture was stirred at 50° C. for 5 h and worked up. The resulting residue was purified by column chromatography (silica, petroleum ether) to afford 1.8 g (95%) of a red-brown solid. mp 55-57° C.; 1H NMR δ 1.17 (t, J=7.5 Hz, 3H), 2.35 (q, J=7.5 Hz, 2H), 4.10 (s, 4H), 4.18 (t, J=2.1 Hz, 2H), 4.40 (t, J=2.1 Hz, 2H), 7.18, 7.64 (AA′BB′, J=8.1 Hz, 2×2H); 13C NMR δ 15.5, 22.3, 67.0, 68.9, 69.5, 70.2, 74. 5, 91.2, 123.3, 133.5, 134.0, 135.8; FAB-MS obsd 439.8721, calcd exact mass 439.8724 (C20H17FeI).