Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C@@H:7]([C:16]([O:18][CH3:19])=[O:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[O:37]=[C:38]1[CH:42]=[CH:41][C:40](=[O:43])[N:39]1[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([NH:51][CH2:52][C:53](O)=[O:54])=[O:50]>CN(C)C=O>[C:12]([O:11][C:9]([NH:8][C@H:7]([C:16]([O:18][CH3:19])=[O:17])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:53](=[O:54])[CH2:52][NH:51][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][N:39]2[C:38](=[O:37])[CH:42]=[CH:41][C:40]2=[O:43])=[CH:21][CH:20]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)CNC(=O)CCCCCN2C(=O)C=CC2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
To a solution of methyl 4-amino-N-(tert-butoxycarbonyl)-L-phenylalaninate (4.1 g, 15.3 mmol, 1 eq.) in dry N,N-dimethylformamide (70 mL) was added N,N′-Dicyclohexylcarbodiimide (2.9 g, 15.3 mmol, 1 eq.) at 0° C. The mixture was stirred at 0° C. for 30 minutes. A solution of 2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)acetic acid (3 g, 10.2 mmol, 0.66 eq.) in dry N,N-dimethylformamide (20 mL) was added at 0° C. The mixture was stirred at room temperature for 3 days. The mixture was filtered. The filtrate was poured into ice water (200 mL) and extracted with EtOAc (200 mL×3). The extract was washed with brine (200 mL), dried over Na2SO4 and concentrated in vacuo to afford #251 (1.8 g, 32.3% yield) as a light yellow solid. HPLC (Protocol Q2) [M+Na+] 567.3, retention time=1.02 min
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH:7]=[CH:8][C:9](O)=[O:10])=[O:4].[BH4-].[Na+].O>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1/[CH:7]=[CH:8]/[CH2:9][OH:10])=[O:4]
Reactant: COC(=O)c1ccccc1C=CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1ccccc1/C=C/CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methoxycarbonylcinnamic acid, m.p. 176° C., was prepared by the method described in Example 2(a) and converted to the acid chloride, m.p. 75°-80° C., by the method described in Example 2(b). A solution of this acid chloride (15.5 g) in ether (250 ml) was added to a stirred suspension of sodium borohydride on alumina (60 g - prepared by addition of a solution of 1 part of sodium borohydride in 2 parts of water to 10 parts of alumina, with cooling, followed by drying under vacuum) in ether (360 ml). The mixture was stirred for 2 hours at room temperature and filtered. The filtrate was washed with 10% sodium carbonate solution, then with saturated sodium chloride solution, dried and evaporated to yield the title compound as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:25]=[CH:26][C:27]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:28]=4)[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.CCOCC>ClCCl>[CH2:33]([N:29]1[CH:28]=[C:27]2[C:31]([CH:32]=[C:24]([C:8]3[CH:9]=[C:10]([CH:11]4[O:16][CH2:15][CH2:14][NH:13][CH2:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:25]=[CH:26]2)=[N:30]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(C3CNCCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
A suspension of tert-butyl 2-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]morpholine-4-carboxylate (680 mg, 1.3 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (4 mL) and the solution allowed to stir for 10 min. Volatiles were removed in vacuo and the residue taken up in 25 mL of 1,2-dichloroethane. This solution was again dissolved in 1,2-dichloroethane and concentrated in vacuo. This process was repeated 2 additional times, yielding a brown semi-solid. Trituration with ether:hexanes provided the desired product 560 mg (99%) as a brown solid; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.93 (s, 1 H), 7.81 (d, 1 H, J=9 Hz), 7.65 to 7.73 (m, 1H), 7.59 (s, 1H), 7.26 to 7.41 (m, 5H), 7.13 (d, 1H, J=9 Hz), 6.76 (s, 1H), 5.65 (s, 2H), 5.09 (dd, 1H, J=10, 2 Hz), 4.12 (dd, 1H, J=6, 2 Hz), 3.85 to 3.94 (m, 1H), 3.65 to 3.76 (m, 1H), 3.15 to 3.23 (m, 1H), 2.98 to 3.08 (m, 1H), 2.80-2.96 (m, 2H); ES-MS m/z 426.2 [M+H]+, HPLC RT (min) 2.11.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH:20]N(C)C)[CH:18]=O)=[CH:13][CH:12]=1.C(O)(=O)C>CO.O>[C:4]([C:6]1[C:7](=[O:8])[NH:9][CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:20]=1)#[N:5]
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c[nH]c1=O
Temperature: 25 °C

Procedure:
To solution of sodium methoxide (7.52 g) in methanol (130 ml) was added cyanoacetamide (5.84 g) followed by 2-(4-chlorophenyl)-3-dimethylaminopropenal and the resulting suspension was refluxed overnight. During this time a yellow solid was formed. The mixture was cooled to room temperature and glacial acetic acid (50 ml) was added followed by water (100 ml). The resulting yellow orange solid was filtered off, washed several times with water and dried to yield 8.1 g of 3-cyano-5-(4-chlorophenyl)-2-pyridinone.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][S:13][CH2:14][CH2:15][OH:16])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C(=O)([O-])[OH:27].[Na+].C(OCC)(=O)C>N1C=CC=CC=1.C1C=CC=CC=1>[C:18]([O:16][CH2:15][CH2:14][S:13][S:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)(=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: O=C([O-])O
Reactant: OCCSSCCc1ccc2c(c1)OCO2
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(OCCSSCCc1ccc2c(c1)OCO2)c1cccnc1
Temperature: 0 °C

Procedure:
4 g of the 2-[{2-(1,3-benzodioxol-5-yl)ethyl}-dithio] ethanol prepared in Example 1 was dissolved in a mixture comprising 20 ml of pyridine and 50 ml of benzene to obtain a solution. 4 g of nicotinyl chloride hydrochloride was added to the solution. The obtained mixture was heated under reflux for 2 hours and poured into ice/water. The obtained mixture was weekly basified with sodium hydrogencarbonate. Ethyl acetate was added to the mixture to carry out the phase separation. The ethyl acetate layer was washed with water five times, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to obtain 5.4 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCCC1.CO>[C:9]([N:8]=[CH:7][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1)#[N:15]
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CN=CNCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
500 mg of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 400 mg of ethyl N2-cyanocarboxyimidate were dissolved in a solvent mixture of tetrahydrofuran (5 ml) with methanol (5 ml) and stirred at 40° C. for 1.5 hours. Then the reaction mixture was distributed into an aqueous solution of potassium carbonate and ethyl acetate. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) and recrystallized from methanol/ethyl acetate. Thus, 170 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:10]3=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[CH3:24][N:15]1[CH2:14][CH2:13][CH2:12][N:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:10]2[CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)c1nc(-c2ccccc2)n2c1CNCCC2
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of intermediate 64A (0.91 g, 3.17 mmol) in 20 mL THF was added formaldehyde (37% in water, 2.36 mL) followed by sodium triacetoxyborohydride (1.34 g, 6.34 mmol) and acetic acid (0.27 mL, 4.76 mmol). The resulting mixture was stirred at room temperature overnight and then quenched with NaHCO3 saturated solution and stirred for 10 minutes. The reaction mixture was concentrated under vacuum and extracted with 10% iPrOH/DCM.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:28]1[CH2:38][O:37][C:36]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=2[O:29]1>C(O)CO>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:33][C:32]3[CH:34]=[CH:35][C:36]4[O:37][CH2:38][CH2:28][O:29][C:30]=4[CH:31]=3)[N:7]=2)=[CH:10][CH:11]=1)[CH3:17]
Reactant: CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: CCOc1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1
Temperature: 200 °C
Yield: 59.1 %

Procedure:
To a solution of 2-chloro-N4-(4-ethyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.93 mmol) in ethylene glycol (3 mL) under nitrogen at room temperature was added i-Pr2EtN, 0.93 mmol) followed by 3,4-ethylenedioxyaniline (0.17 g, 1.12 mmol). The reaction mixture was heated to 200° C. for 5 h and then cooled to room temperature. The mixture was partitioned between H2O (20 mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude brown solid was purified by chromatography (2:1 CHCl3/EtOAc) to afford N4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (0.21 g, 60%) as a tan solid: Rf 0.42 (4:1 CHCl3/EtOAc); mp 163.8–167.2° C. (DSC); 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=2.8 Hz, 1H), 7.50–7.45 (m, 2H), 7.17 (d, J=2.5 Hz, 1H), 6.92–6.86 (m, 3H), 6.80–6.75 (m, 2H), 6.64 (bs, 1H), 4.26–4.21 (m, 4H), 4.03 (q, J=7.0, 2H), 1.42 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.1, 150.6, 143.6, 142.8, 140.3, 140.0, 139.5, 139.3, 134.0, 130.8, 123.2, 117.2, 115.1, 113.6, 109.4, 64.6, 64.0, 15.1; IR (ATR) 3403 cm−; ESI MS m/z 383 [C20H19FN4O3+H]+; HPLC (Method A) 98.1% (AUC), tR=12.0 min. Anal. Calcd for C20H19FN4O3: C, 62.82; H, 5.01; N, 14.65. Found: C, 62.06; H, 5.01; N, 14.35.
Reaction SMILES: [CH:1]([N:3]([CH3:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)=[O:2].[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:39]=2[S:40][C:41]=1[C:42](Cl)=[O:43]>>[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:39]=2[S:40][C:41]=1[C:42]([N:19]([CH2:18][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH:1]=[O:2])[CH3:35])=[CH:5][CH:6]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17])[CH:20]1[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[CH2:22][CH2:21]1)=[O:43]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(N(C)C=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(N(C)C=O)cc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 52 (200 mg, 0.42 mmol) is treated with acid chloride 6 (120 mg, 0.49 mmol) using Method D to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH2:17]([OH:22])[CH2:18][CH2:19][CH2:20][OH:21].OCCCOCC1C=CC=C(C)C=1C(OC(C)(C)C)=O>>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][O:22][CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: OCCCCO
Reactant: Cc1cccc(CBr)c1C(=O)OC(C)(C)C
Agent: Cc1cccc(COCCCO)c1C(=O)OC(C)(C)C
Product: Cc1cccc(COCCCCO)c1C(=O)OC(C)(C)C

Procedure:
tert-Butyl 2-(4-hydroxybutoxymethyl)-6-methylbenzoate is prepared from tert-butyl 2-bromomethyl-6-methylbenzoate and butane-1,4-diol in analogy to the synthesis of tert-butyl 2-(3-hydroxypropoxymethyl)-6-methylbenzoate.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:23][C:24]([OH:26])=[O:25])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:35][C:36]([NH2:38])=[NH:37])=[N:11][CH:10]=1.[H-].[Na+].[C:41](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)CC1C=CC=CC=1C)([CH3:44])([CH3:43])[CH3:42]>COCCOC.CCOC(C)=O>[C:41]([O:25][C:24](=[O:26])[CH2:23][N:22]([S:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:35][C:36]([NH2:38])=[NH:37])=[CH:17][CH:16]=1)(=[O:20])=[O:21])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: Cc1ccccc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: Cc1ccccc1CN(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 44.4 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine trifluoroacetate ##STR20## Guanidine hydrochloride (120 mg, 1.26 mmol) was added in one portion to a suspension of NaH (32 mg, 80% dispersion by wt in mineral oil, 1.06 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine t-butyl ester (200 mg, 0.405 mmol) was added and the mixture heated at 90° C. for 2 h. The cooled mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-CH2Cl2 (50:50), then CH2Cl2, and finally CH2Cl2 -MeOH-0.880NH3 (95:5:0.5) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine t-butyl ester (94 mg, 0.18 mmol) as an off-white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C1C=C(O)C([S:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=CC=1.[OH-].[Na+]>O.ClC1C=CC=CC=1Cl>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[C:4]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:5]=1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccccc1O
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 91.2 %

Procedure:
A mixture of 290 g (3.09 moles) of phenol, 146 g of 98% sulfuric acid and 150 g of o-dichlorobenzene is heated with stirring. When the temperature of the reaction system reaches about 150° C., the mixture begins to boil, giving off an azeotropic mixture of water and o-dichlorobenzene, which is condensed and separated into two phases, i.e., water and o-dichlorobenzene. The o-dichlorobenzene is continuously returned to the reaction mixture. With continuous heating, when the amount of the aqueous phase reaches 52 ml, the temperature of reaction mixture is about 180° C. Subsequently o-dichlorobenzene containing small amounts of water and phenol is completely distilled off over a period of 3 hours by reducing a pressure of the reaction system to produce the dried reaction mixture in a solid state, while adjusting the temperature to 175° to 185° C. When analyzed by gas chromatography, the dried reaction mixture is found to contain 0.9% by weight of 2,4'-dihydroxydiphenylsulfone based on 4,4'-dihydroxydiphenylsulfone present therein (hereinafter referred to as isomer content). A solution of 62 g of sodium hydroxide in 3.5 l of water is added to the residue, 5 g of active carbon is added to the solution, the mixture is filtered and the filtrate is neutralized with sulfuric acid. The resulting crystals are filtered off, then washed with water and dried, giving 332 g of 4,4'-dihydroxydiphenylsulfone, melting at 248° C., in a yield of 91.2% based on the sulfuric acid starting material. When analyzed by gas chromatography, the product is found to contain 0.8% of isomer content.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][CH2:32][CH2:33]Br>CN(C=O)C>[Br:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCBr
Temperature: 50 °C
Yield: 65.7 %

Procedure:
To a solution of 7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (1 g, 3.2 mmol), (prepared as described for the starting material in Example 107), in DMF (50 ml) was added powdered potassium carbonate (1.32 g, 9.6 mmol) and 1,3-dibromopropane (6.43 g, 32 mmol). The reaction was heated at 50° C. for 2 hours. The inorganic material was filtered off and then the DMF removed. The residue was partitioned between methylene chloride/water. The organics were separated, dried over MgSO4, filtered, evaporated in vacuo and purified by flash chromatography eluting from methylene chloride to 5% methanol/95% methylene chloride. The product was concentrated in vacuo, triturated with ether and the resulting solid filtered to give 7-(3-bromopropoxy)-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (900 mg, 66%) as a white solid.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]1[CH:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][CH:13]1[OH:21].CCOCC>ClCCl>[CH2:12]1[CH:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][C:13]1=[O:21]
Reactant: OC1CC2CCCCC2C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CC2CCCCC2C1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To 33.6 g (155 mmol) of finely ground pyridinium chlorochromate, stirred in 300 mL of dry dichloromethane, was added 7.0 g (50 mmol) of (2 alpha and 2 beta)-octahydro-1H-inden-2-ol in 30 mL of dichloromethane. After stirring for 2 h at 20° C., 300 mL of ether was added, the organic solution decanted from the gummy precipitate and the latter extracted with 5×100 mL of ether. The combined organic solutions were filtered through 450 g of silica gel and the latter washed with ether. Concentration of the filtrates and distillation gave 5.5 g (80%) of (3a alpha, 7a alpha)-octahydro-2H-inden-2-one bp 110°-112° C. (18 mm); TLC Rf of 0.29 (SiO2, dichloromethane, molybdophosphoric acid-colorless on blue-green).
Reaction SMILES: C([C:5]1[C:6](=O)[NH:7][CH2:8][C:9](=[O:20])[N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=12)(C)(C)C.O=P(Cl)(Cl)Cl.[CH3:27][O:28][CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1>ClCCCl.C(Cl)Cl>[C:12]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH2:19][N:10]1[C:9](=[O:20])[CH2:8][N:7]=[C:6]([N:33]3[CH:34]=[C:30]([CH2:29][O:28][CH3:27])[N:31]=[CH:32]3)[CH:5]=[C:11]12)([CH3:17])([CH3:13])[CH3:11]
Reactant: CC(C)(C)C1=C2c3ccccc3CCN2C(=O)CNC1=O
Reactant: COCc1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: COCc1cn(C2=NCC(=O)N3CCc4c(cccc4C(C)(C)C)C3=C2)cn1
Temperature: 110 °C
Yield: 33.7 %

Procedure:
Example 125. A solution of -(tert-butyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (370 mg, 1.30 mmol) in DCE (20 mL) was treated with POCl3 (0.24 mL, 2.60 mmol) and the mixture was heated to 110° C. for 1 h. The mixture was then allowed to cool to RT, diluted with DCM and washed with H2O. The org. phase was then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was taken up in DCE (20 mL) and 4-(methoxymethyl)-1H-imidazole (438 mg, 3.90 mmol) was then added. The mixture was heated to 110° C. for 1 h, and then allowed to cool to RT, diluted with DCM and washed with H2O. The org. layer was then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) and SFC (column: PPU 5 μm, 250×30 mm, 60 A, Princeton; eluent: isocratic 5% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm) gave the title compound (83 mg). UPLC-MS: MS 379.2 (M+H+); UPLC rt 1.04 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.38 (s, 9 H); 3.10-3.20 (m, 2 H); 3.22 (br s, 3 H); 3.63 (m, 2 H); 4.25 (m, 4 H); 6.86 (d, J=1.96 Hz, 1 H); 7.31 (s, 1 H); 7.49 (d, J=8.21 Hz, 1 H); 7.54-7.69 (m, 2 H); 8.17 (d, J=1.56 Hz, 1 H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][OH:8])(=[O:4])=[O:3].N(C(N1CCCCC1)=O)=N[C:11](N1CCCCC1)=[O:12].[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][C:39](O)=[C:40](OC)[CH:41]=3)[N:36]=[CH:35][N:34]=2)=[C:30]([F:48])[CH:29]=1.C(P(CCCC)CCCC)CCC.Cl>C(Cl)Cl.CC(C)=O.CO.C(Cl)Cl>[ClH:27].[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:40][CH:41]=3)[N:36]=[C:35]([O:12][CH3:11])[N:34]=2)=[C:30]([F:48])[CH:29]=1
Reactant: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Reactant: CS(=O)(=O)CCCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1nc(Nc2ccc(Cl)cc2F)c2ccc(OCCCS(C)(=O)=O)cc2n1
Reaction time: 18 h
Yield: 57.2 %

Procedure:
3-(Methylsulphonyl)propan-1-ol (0.6 g, 4.3 mmol) followed by 1,1′-(azodicarbonyl)dipiperidine (4.2 g, 16 mmol) in portions were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.5 g, 4.7 mmol), (prepared as described for the starting material in Example 2), and tributylphosphine (4.0 ml, 16 mmol) in methylene chloride (50 ml) under nitrogen. The mixture was stirred for 18 hours, the resulting precipitate was collected by filtration and dried to give crude product (1.36 g). The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol (a gradient from 100/0 to 90/10). The semi-purified product was triturated with acetone and the solid product collected by filtration and dried to give further crude product (0.53 g). The filtrate from the trituration was repurified by column chromatography as before to give further crude product (0.23 g). The crude products were combined and dissolved in acetone/methanol/methylene chloride and ethereal hydrogen chloride (6 ml of a 1M solution) added. The precipitated product was collected by filtration and recrystallised from methanol/methylene chloride/hexane to give 4-(4-chloro-2-fluoroanilino)-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline hydrochloride (640 mg, 29%). m.p. >250° C.