Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]2=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)CNC
Reactant: Cc1ccc(N=C=S)cc1Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(N2C(=O)CN(C)C2=S)cc1Cl
Yield: 57.1 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 18.3 g of 3-chloro-4-methylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (14.5 g) as an off-white solid, m.p. 178°-180° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.89; H, 4.20; N, 10.95. Mass spectrum (+FAB, [M+H]+) m/z 255/257.
Reaction SMILES: F[C:2](F)(C1C=CC(F)=CC=1)C1N=C(NC2C=C(C)NN=2)C2C(=CC(F)=CC=2)N=1.[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][C:36](F)=[CH:37][CH:38]=2)[N:33]=[C:32]([C:41]([F:50])([F:49])[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[N:31]=1>>[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][C:36]([CH3:2])=[CH:37][CH:38]=2)[N:33]=[C:32]([C:41]([F:49])([F:50])[C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[N:31]=1
Reactant: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cc3)nc3cc(F)ccc23)n[nH]1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccc(F)cc3n2)cc1
Product: Cc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Yield: 13 %

Procedure:
2-(Difluoro(4-fluorophenyl)methyl)-7-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine was obtained according to the procedure described in Example 20 for preparation of 2-(difluoro(4-fluorophenyl)methyl)-7-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, substituting 4-chloro-2-(difluoro(4-fluorophenyl)methyl)-7-fluoroquinazoline in Example 20 with 4-chloro-2-(difluoro (4-fluorophenyl)methyl)-7-methylquinazoline (13% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.50 (s, 3H), 6.30 (s, 1H), 7.34 (t, 2H), 7.47 (m, 1H), 7.71-7.66 (m, 3H), 8.56 (d, 1H), 10.59 (s, 1H), 12.20 (bs, 1H); LC-MS (ESI) m/z 384 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=2)O1>>[O:14]1[CH2:15][CH2:16][N:11]([C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:25]3[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[N:3]=2)[CH2:12][CH2:13]1
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncsc3n2)cn1

Procedure:
4-(5-Chlorothiazolo[5,4-d]pyrimidin-7-yl)morpholine 14 was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to give 131 after purification by reverse HPLC.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:4]1.Cl[C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)C>[CH3:15][O:14][C:12]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:3]([NH:2][C:17]1[C:18]3[C:25]([CH3:26])=[CH:24][S:23][C:19]=3[N:20]=[CH:21][N:22]=1)[CH2:4]2)=[O:13]
Reactant: COC(=O)c1cccc2c1CC(N)C2
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cccc2c1CC(Nc1ncnc3scc(C)c13)C2

Procedure:
Using 2-(tert-butoxycarbonylamino)-4-methoxycarbonylindan (45 mg, 0.15 mmol) synthesized in the above Reference Production Example 7, 4N hydrochloric acid-dioxane (0.7 ml) and acetic acid (2.1 ml), a similar procedure to Production Example 213 was carried out to obtain 2-amino-4-methoxycarbonylindan hydrochloride. Then, using the 2-amino-4-methoxycarbonylindan hydrochloride, 4-chloro-5-methylthieno[2,3-d]pyrimidine (28 mg, 0.15 mmol), triethylamine (63 μl, 0.45 mmol), and ethanol (1 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (15 mg, 0.044 mmol) having the following physical properties:
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)=[N:11][CH:12]=1.C([N:27]([CH:31]([CH3:33])C)[CH:28]([CH3:30])C)C.N1CCCC1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:27]3[CH2:28][CH2:30][CH2:33][CH2:31]3)=[CH:19][CH:18]=2)=[N:11][CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: OCc1ccc(CCC#Cc2ccc(Br)cn2)cc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.24 mL (3.04 mmol) methanesulphonic acid chloride are added to a solution, cooled to 0° C., of 800 mg (2.53 mmol) {4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol in 17 mL DCM and then a solution of 0.52 mL ethyldiisopropylamine in 3 mL DCM is added dropwise. The mixture is stirred for a further 30 min at 0° C., 0.51 mL (6.08 mmol) pyrrolidine is added, the reaction mixture is heated to RT and kept at this temperature for 5 h. To complete the reaction another 0.26 mL (3 mmol) pyrrolidine are added and stirred for 1 h at RT. The mixture is evaporated down i.vac., combined with 10 mL water and 20 ml EtOAc, acidified with 1 M HCl and the organic phase is separated off. The aqueous phase is made alkaline with 2 M Na2CO3 solution, extracted with 20 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the desired product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([NH:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([S:40](Cl)(=[O:42])=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([S:40]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:21][C:19](=[O:20])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:29][CH:30]([CH3:32])[CH3:31])(=[O:42])=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NNc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(=O)(=O)Cc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Yield: 77.8 %

Procedure:
In an analogous manner to that described in Example 1, part (ii), starting from 0.3 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-2′-phenylvalerohydrazide and 0.543 g of benzylsulphonyl chloride there was obtained 0.316 g of (E)-2′-(benzylsulphonyl)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-2′-phenylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>ClCCl>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:23])[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(O)ccn1Cc1ccccc1
Solvent: ClCCl
Product: O=c1c(Br)c(O)ccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of N-benzyl-4-hydroxy-2-pyridone ((0.75 g, 3.7 mmol), NBS (0.7 g, 1.05 mmol) in dichloromethane was stirred at room temperature for 1.5 h under argon atmosphere. It was diluted with dichloromethane (25 mL), cooled and filtered. The solids were washed with dichloromethane and dried in vacuo. The filtrate and the washings were combined and washed with water, dried (Na2SO4), filtered, and concentrated to dryness. The resulting residue was washed with EtOAc, and dried in vacuo to give a combined mass of 0.65 g of the title compound as a white powder: 1H NMR (CD3OD) δ: 7.54 (d, 1H, J=7.6 Hz), 7.27 (m, 5H), 6.12 (d, 1H, J=7-6 Hz), 5.15 (s, 2H); ES-MS: m/z=280 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)=[O:6].[O-2].[Ca+2].[H][H]>[Pd].COCCO>[OH:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1)=[O:6]
Reactant: O=C(NCCO)c1cnccn1
Reactant: [H][H]
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: COCCO
Product: O=C(NCCO)C1CNCCN1
Yield: 100 %

Procedure:
A mixture of 53.7 parts of N-(2-hydroxyethyl)-2-pyrazinecarboxamide, 20 parts of calcium oxide and 500 parts of 2-methoxyethanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 55.4 parts (100%) of N-(2-hydroxyethyl)-2-piperazinecarboxamide as a residue (intermediate 23).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C1([Mg]Br)C=CC=CC=1.C(OCC)C.[F:21][C:22]1[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>ClCCl>[F:21][C:22]1[CH:29]=[C:28]([CH:30]([OH:31])[C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: Cn1cncc1I
Agent: Br[Mg]c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-iodo-1-methyl-1H-imidazole (250 mg, 1.2 mmol) in dichloromethane (2 mL) at 0° C. was treated with 3M phenylmagnesium bromide in diethyl ether (0.4 mL, 1.2 mmol), stirred for 30 minutes, warmed to room temperature, stirred for 30 minutes, cooled to 0° C. and treated with a solution of Example 52C (150 mg, 1.0 mmol) in dichloromethane (1 mL). The mixture was warmed to room temperature, stirred for 2 days, and quenched with ethyl acetate and saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate (2×100 mL), and the combined organic layers were dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in 1:1 ethyl acetate/diethyl ether, filtered, rinsed with 1:1 ethyl acetate/diethyl ether and dried to provide the desired product. 1H NMR (400 MHz, CD3OD) δ 7.91 (dd, 1H), 7.56 (s, 1H), 7.51 (d, 1H), 7.42-7.38 (m, 1H), 6.42 (s, 1H), 6.28-6.24 (m, 1H), 5.93-5.91 (m, 1H), 3.52 (s, 3H).
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[N:10]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[C:25]([CH3:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[NH:36]1[CH2:44][CH2:43][CH:39]([C:40]([NH2:42])=[O:41])[CH2:38][CH2:37]1>O>[NH2:30][C:27]1[N:26]=[C:25]([CH3:31])[C:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([N:36]4[CH2:44][CH2:43][CH:39]([C:40]([NH2:42])=[O:41])[CH2:38][CH2:37]4)[N:10]3[CH2:32][CH:33]3[CH2:35][CH2:34]3)=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)=[CH:29][N:28]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(C(N)=O)CC3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and isonipecotamide (191 mg, 1.5 mmol) and the resulting mixture was stirred at 120° C. for 2.5 hours. The reaction mixture was left standing to cool followed by the addition of water and the insoluble matter was collected by filtration and dried to give the title compound (85 mg, 69%) as a pale yellow solid.
Reaction SMILES: Cl.C(OC(=O)[C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1)C.CO[CH:17](OC)[CH2:18]CCCl>C(O)C.O>[NH:12]1[C:9]2[C:10](=[CH:11][CH:6]=[CH:7][CH:8]=2)[CH:18]=[CH:17]1
Reactant: COC(CCCCl)OC
Reactant: CCOC(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: c1ccc2[nH]ccc2c1
Yield: 68.5 %

Procedure:
A solution of ethyl-p-hydrazinobenzoate hydrochloride (10 g, 46 mmol) and 4-chlorobutanal dimethyl acetal (7.8 g, 46 mmol) in ethanol/water (5:1, 500 ml) was heated at reflux for 2 h. The solvent was removed under vacuum and the residue chromatographed through silica-gel eluting with dichloromethane/ethanol/ammonia (40:8:1) to give the title-indole as an oil (3.69 g). The hydrogen maleate salt was prepared, mp 127° C.; (Found: C, 59.46; H, 5.96; N, 8.47. C13H16N2O2.C4H4O4 requires C, 59.68; H, 5.93; N, 8.54%), m/e 232 (M+), δ(360 MHz, D2O) 1.43 (3H, t, J=7.1 Hz, Me); 3.21 (2H, t, J=7.0 Hz, CH2); 3.37 (2H, t, J=7.0 Hz, CH2); 4.42 (2H, q, J=7.1 Hz, CH2); 6.23 (2H, s, maleate-H); 7.40 (1H, s, indole-H); 7.56 (1H, d, J=8.8 Hz, aromatic-H); 7.88 (1H, dd, J=1.6 and 8.8 Hz, aromatic-H); 8.38 (1H, d, J=1.6 Hz, aromatic-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]=O)[CH2:12][CH2:11]1)=[O:8].[CH2:20]([C:22]1[NH:26][N:25]=[C:24]([NH2:27])[C:23]=1[CH3:28])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][NH:27][C:24]2[C:23]([CH3:28])=[C:22]([CH2:20][CH3:21])[NH:26][N:25]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: CCc1[nH]nc(N)c1C
Reactant: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1[nH]nc(NC[C@H]2CC[C@H](NC(=O)c3cc(Cl)cnc3C)CC2)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture comprising trans-5-chloro-N-(4-formyl-cyclohexyl)-2-methyl-nicotinamide Intermediate E) (100 mg, 0.30 mmol) and 5-ethyl-4-methyl-1H-pyrazol-3-amine (37.5 mg, 0.30 mmol) in DCM (5 ml) was treated with sodium triacetoxyborohydride (95 mg, 0.45 mmol). The reaction mixture was stirred at RT for 18 hours and then partitioned between DCM and sat. NaHCO3. The organic phase was passed through a phase separator and the solvent was removed in vacuo. The resulting crude product was triturated in EtOAc, filtered and dried to afford the title compound; 1H NMR (d6-DMSO, 400 MHz) δ 10.87 (1H, s), 8.53 (1H, m), 8.40 (1H, m), 7.80 (1H, m), 4.43 (1H, m), 3.69 (1H, m), 2.90 (2H, t), 2.50 (3H, s), 2.40 (2H, q), 1.88 (4H, m), 1.73 (3H, s), 1.53 (1H, m), 1.21 (2H, m), 1.09 (3H, t), 1.00 (2H, m); LCMS Rt=2.06 min, [M+H]+390 Method LowpH_v002.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28][CH2:29][CH2:30]Br)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1.[OH:34][C@@H:35]([CH3:46])[CH2:36][NH:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C(#N)C>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28][CH2:29][CH2:30][N:37]([CH2:38][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:36][C@@H:35]([OH:34])[CH3:46])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OCCBr
Reactant: C[C@H](O)CNCC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OCCN(CC(=O)OC(C)(C)C)C[C@H](C)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.25 ml of diisopropylethylamine are added to 650 mg of 4-[(3-bromo-phenyl)amino]-6-(2-bromoethoxy)-7-methoxy-quinazoline and 1.10 g of tert.butyl (S)-(2-hydroxy-propylamino)-acetate in 15 ml of acetonitrile. The reaction mixture is stirred overnight at 50° C. Since no reaction can be detected, the reaction mixture is concentrated by evaporation, combined with 20 ml of N,N-dimethylformamide and stirred for eight hours at 60° C. Then the temperature is increased to 80° C. After another eight hours the reaction is complete. The reaction mixture is concentrated by evaporation and chromatographed over a silica gel column with ethyl acetate as eluant. The desired product is obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=[O:6].C(Cl)Cl.F[B-](F)(F)F.[CH2:20]([O+](CC)CC)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](=[NH:7])[O:6][CH2:20][CH3:21]
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1ccc(Cl)c(Cl)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dichlorobenzamide (139 g.; 0.73 mole) suspended in 600 ml. of methylene chloride is added to 150 g. (0.8 mole) of triethyloxonium fluoroborate in 100 ml. of methylene chloride cooled in an ice-bath to 0° C. over a period of 10-15 min. At the end of the addition, the mixture is allowed to stir at room temperature overnight. The mixture is again cooled in an ice-bath and 141 g. of 50% potassium carbonate in water is added over 30 min. The mixture is stirred for 15 min., the methylene chloride layer separated and the solids washed with methylene chloride. The combined organic layer and washings are dried over sodium sulfate and concentrated in vacuo to a yellow oil which is treated with hexane. A small amount of solids are filtered and the filtrate concentrated to give, after drying in vacuo, 140 g. of the desired imino ether, m.p. 62°-64° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42]N(C)C)=[O:39])=[CH:36][C:35]=1[O:48][CH3:49]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][CH2:6][N:7]([CH3:16])[CH3:8])=[O:39])=[CH:36][C:35]=4[O:48][CH3:49])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1N
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 66.5 %

Procedure:
A mixture of 0.0638 g (0.211 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0601 g (0.32 mmole) of toluenesulfonic acid monohydrate, 0.053 g (0.211 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 20 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) and then recrystallization from acetonitrile to give 0.0363 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-9) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][C:21]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=4[N:28]=3)[C:14]2=[O:29])[CH2:9][CH2:8]1)=[O:4].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][C:21]4[CH2:27][CH2:26][N:25]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:24][CH2:23][C:22]=4[N:28]=3)[C:14]2=[O:29])[CH2:11][CH2:12]1)=[O:4]
Reactant: ClCc1ccccc1
Reactant: COC(=O)CC[C@H]1CC[C@H](N2CCN(c3cnc4c(n3)CCNCC4)C2=O)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CC[C@H]1CC[C@H](N2CCN(c3cnc4c(n3)CCN(Cc3ccccc3)CC4)C2=O)CC1

Procedure:
1.5 g of 1-[trans-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]-3-(6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)imidazolidin-2-one, 480 mg of benzyl chloride, 520 mg of N-ethyldiisopropylamine and 100 mg of sodium iodide are heated under reflux in 20 ml of acetonitrile for 1 hour. The mixture is cooled, and the solid is filtered off with suction and purified by chromatography on an alumina column with methylene chloride/methanol (99:1).
Reaction SMILES: [OH:1][CH:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14](S(C)(=O)=O)[N:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:1][CH:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4])[N:13]=1
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1nc(C)cc(C)n1)C(C)(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
2.9 g of methyl 2-hydroxy-3,3-dimethybutyrate, 4.1 g of 4,6 -dimethyl-2-methylsulfonylpyrimidine and 3.3 g of potassium carbonate were added to 50 ml of N,N-dimethylformamide, and the mixture was stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature, poured into water and extracted with 100 ml of ethyl acetate. The organic layer was washed twice with a sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The liquid substance thereby obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =6/1) to obtain 4.2 g of the desired product.
Reaction SMILES: C[O:2][C:3](=O)[NH2:4].[CH2:6]([CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH2:14])[CH3:7].N>O1CCOCC1>[CH2:6]([CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:3](=[O:2])[NH2:4])[CH3:7]
Reactant: COC(N)=O
Reactant: CCC1CCCC1CN
Agent: N
Solvent: C1COCCO1
Product: CCC1CCCC1CNC(N)=O
Reaction time: 2 h

Procedure:
4.33 g of N-[4-(β-<3-methoxy-5-chlorothiophene-2-carboxamido>-ethyl)-benzenesulfonyl]-carbamic acid methyl ester (melting point 186° - 188° C) were dissolved in 100 ml of dioxane and, after addition of 1.2 g of 2-ethyl-cyclopentylmethylamine, kept for 2 hours under reflux. The clear solution was poured into dilute aqueous ammonia solution, filtered and acidified with 2N-hydrochloric acid. The N-[4-(β-<3-methoxy-5-chlorothiophene-2-carboxamido>-ethyl)-benzenesulfonyl]-N'-(2-ethyl-cyclopentyl-methyl)-urea so obtained was found to melt at 160° - 161° C after recrystallization from methanol.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=O)[CH:2]=[CH2:3].[CH2:10](O)CCC.O>C(OCCCC)(=O)C>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:10]
Reactant: CCCCO
Reactant: C=CC(=O)OCCCC
Solvent: O
Solvent: CCCCOC(C)=O
Product: CCCCOCCCC

Procedure:
The organic phase contained from 75 to 85% by weight of butyl acrylate, from 14 to 20% by weight of butanol, from 2 to 3% by weight of water, 1500 ppm of butyl acetate. The excess water corresponding to the conversion in the reaction was removed from the system through line 27. 5% by weight of the bottom product (product II), based on the amount of starting materials fed to the esterification, was discharged via line 28 and fed to a stirred vessel IV. There, the product was evaporated batchwise at ambient pressure and 180° C. until the viscosity rose distinctly. The starting materials butanol and acrylic acid still present therein and the product butyl acrylate were first distilled off. The amount of distillate was up to about 65% by weight, based on the amount fed in. In the subsequent cracking of the high boilers, the bottom discharge was evaporated to about 15% of its original mass, and low-boiling by-products such as butenes and dibutyl ether were formed to a small extent only toward the end. The condensed vapors from the cracking in the stirred vessel IV consisted essentially of acrylic acid, butyl acrylate, butanol and water. This liquid was fed directly to the bottom of the column I for the high-boiler separation. A further rectification was not carried out.