Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[Br:15][C:16]1[CH:20]=[N:19][N:18]([CH3:21])[C:17]=1[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]([CH3:36])([N+:33]([O-])=O)[CH3:32])[NH2:25].C(N(CC)C(C)C)(C)C>ClCCl>[NH2:33][C:31]([CH3:36])([CH3:32])[CH2:30][O:29][C:28]1[CH:27]=[CH:26][C:24]([NH:25][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=2)=[CH:23][C:22]=1[C:17]1[N:18]([CH3:21])[N:19]=[CH:20][C:16]=1[Br:15]
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(OC(F)(F)F)c2)ccc1OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
3-Trifluoromethoxybenzoyl chloride (12 mg, 0.06 mmol) was added to a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 1 h, the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was added followed by zinc dust (33 mg) and the mixture was stirred at room temperature. After 4 h, the suspension was made basic with ammonium hydroxide and extracted twice with ethyl acetate. The combined extracts were evaporated to dryness, purified by preparative LCMS and lyophilized to give the product (21 mg, 81%) as a TFA-salt. LCMS m/z (%)=529.3 (M+H 81Br 76.1%), 527.5 (M+H 79Br 64.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 3 H), 1.18 (s, 3 H), 3.67 (s, 3 H), 3.84 (d, J=9.85 Hz, 1 H), 4.00 (d, J=9.85 Hz, 1H), 7.30 (d, J=9.09 Hz, 1 H), 7.60-7.65 (m, 1 H), 7.67 (s, 1 H), 7.68-7.73 (m, 2 H), 7.85-7.93 (m, 4 H), 7.95 (dd, J=8.97, 2.65 Hz, 1 H), 8.01 (d, J=7.83 Hz, 1 H), 10.48 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:23]2=[CH:24][CH:25]=[N:26][CH:27]=[C:22]2[C:5]2[C:6]([OH:21])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:29].[N:30]1([CH2:36][CH2:37][CH2:38][C:39](O)=[O:40])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:29].[CH3:28][C:2]1([CH3:1])[C:23]2=[CH:24][CH:25]=[N:26][CH:27]=[C:22]2[C:5]2[C:6]([O:21][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CC(CCCc1ccccc1)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CC(CCCc1ccccc1)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-[5-phenyl-2-pentyl]-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-[5-phenyl-2-pentyl]-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: COC1C=C2C(=CC=1)CC(=O)CC2.C1([PH2](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41]([CH:45]([CH3:51])[C:46]([O:48]CC)=[O:47])=[CH:40][CH:39]=[CH:38]2>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41]([CH:45]([CH3:51])[C:46]([OH:48])=[O:47])=[CH:40][CH:39]=[CH:38]2
Reactant: CCOC(=O)C(C)c1cccc2cc(OC)ccc12
Agent: COc1ccc2c(c1)CCC(=O)C2
Agent: c1ccc([PH2](c2ccccc2)c2ccccc2)cc1
Product: COc1ccc2c(C(C)C(=O)O)cccc2c1

Procedure:
Thus, for example, by reacting 6-methoxy-2-tetralone with the triphenylphosphorane derived from ethyl-2-halopropionate, 2,2-(1'-carbethoxyeth-1',1'-ylidene)-6-methoxytetralin is prepared. Dehydrogenation thereof provides ethyl 6-methoxynaphthyl-α-methylacetate which upon hydrolysis affords 6-methoxynaphthyl-α-methylacetic acid.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:27]=O>CO>[NH2:7][C:6]1[C:8]([CH3:13])=[CH:9][C:10]([S:12][CH2:27][N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: C=O
Solvent: CO
Product: Cc1cc(SCN(c2ccccc2)c2ccccc2)cc(C(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
To a stirred solution of 4.5 g (23 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline and 3.9 g (23 mmol) of diphenylamine in 30 mL of methanol at -5° C. is added 0.9 g (23 mmol) of formaldehyde as a 37% aqueous solution (1.9 mL). The reaction mixture is stirred for 72 hours at room temperature and then is heated for 5 hours at 50°-55° C. The solvent is removed in vacuo and the residue is purified by flash column chromatography (silica gel, 9:1, heptane:ethyl acetate eluent) to give 3.9 g (45%) of the title compound as a colorless liquid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4].[NH3:14]>O.C(O)C>[NH2:14][CH2:2][C:3]([NH:5][C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4]
Reactant: N
Reactant: CCCCCC(C)(C)NC(=O)CCl
Solvent: CCO
Solvent: O
Product: CCCCCC(C)(C)NC(=O)CN
Reaction time: 0.5 h

Procedure:
A suspension of 2-Chloro-N-(1,1-dimethylhexyl)acetamide (2.5 g, 12 m mol) in a mixture of water (50 ml) and ethanol (50 ml) was saturated in ammoniain the cold and held at room temperature for two days with the occasional passage of ammonia. The mixture was evaporated to a gum which was partially dried by azeotroping with ethanol then 40-60 petrol. The residuewas dissolved in chloroform (50 ml) and stirred with sodium carbonate (2 g)and water (10 ml) for 1/2 hour. The organic phase was then separated, driedover magnesium sulphate, evaporated to a yellow oil and distilled to give 2-amino-N-(1,1-dimethylhexyl)acetamide as a colourless oil, b.p. 109°-113° C. at 0.4 mm Hg.
Reaction SMILES: C(OC(N1C(C(=O)N[C@H](C(OC)=O)CC2C=CC(C3C=CC(C#N)=CC=3)=CC=2)CC2C=C3C([O:13][C@@H:14]([C:46]4[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=4)C(=O)N3)=CC=2C1)=O)(C)(C)C.Cl.C[O:55][C:56](=[O:111])[C@@H:57]([NH:73][C:74]([CH:76]1[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@@H:83]([C:91]4[CH:96]=[CH:95][C:94]([O:97][CH2:98][C:99]5[CH:104]=[CH:103][C:102]([O:105][CH3:106])=[C:101]([C:107]([F:110])([F:109])[F:108])[CH:100]=5)=[CH:93][CH:92]=4)[C:84](=[O:90])[NH:85]3)=[CH:80][C:79]=2[CH2:78][NH:77]1)=[O:75])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][C:68]([C:71]#[N:72])=[CH:67][CH:66]=2)=[CH:61][CH:60]=1>>[C:14]([N:77]1[CH:76]([C:74]([NH:73][C@@H:57]([CH2:58][C:59]2[CH:60]=[CH:61][C:62]([C:65]3[CH:70]=[CH:69][C:68]([C:71]#[N:72])=[CH:67][CH:66]=3)=[CH:63][CH:64]=2)[C:56]([OH:55])=[O:111])=[O:75])[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@@H:83]([C:91]4[CH:92]=[CH:93][C:94]([O:97][CH2:98][C:99]5[CH:104]=[CH:103][C:102]([O:105][CH3:106])=[C:101]([C:107]([F:110])([F:108])[F:109])[CH:100]=5)=[CH:95][CH:96]=4)[C:84](=[O:90])[NH:85]3)=[CH:80][C:79]=2[CH2:78]1)(=[O:13])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(O)cc1)C(=O)N3
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(OC)c(C(F)(F)F)c2)cc1)C(=O)N3
Agent: Cl
Product: COc1ccc(COc2ccc([C@@H]3Oc4cc5c(cc4NC3=O)CC(C(=O)N[C@@H](Cc3ccc(-c4ccc(C#N)cc4)cc3)C(=O)O)N(C(=O)c3ccccc3)C5)cc2)cc1C(F)(F)F

Procedure:
(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-(4-hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester was converted to (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid methyl ester hydrochloride following the general procedure L and C. Title compound (9 mg) was prepared from (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid methyl ester hydrochloride following general procedures F and B. LC-MS (m/z): 882.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11]O>>[CH3:11][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CO
Reactant: Cc1cnc(C(=O)O)cn1
Product: COC(=O)c1cnc(C)cn1

Procedure:
treating 5-methylpyrazine-2-carboxylic acid of the formula VIII: ##STR10## with methanol under reflux to obtain 5-methylpyrazine-2-carboxylic acid methyl ester of the formula VIII A ##STR11## ii) reacting 5-methylpyrazine-2-carboxylic acid methyl ester of the formula VIII A with 2-phenylethylamine of the formula II: ##STR12## at 100° to 200° C. to obtain 5-methylpyrazine 2-(2-phenylethyl) carboxamide of the formula IX: ##STR13## iii) chlorosulfonating the 5-methylpyrazine-2(2-phenylethyl)carboxamide of the formula IX with chlorosulfonic acid at 0°-45° C. to obtain [N-[2-[4-Chlorosulfonyl) phenyl]ethyl]-5-methylpyrazine carboxamide] of the formula X: ##STR14## iv) and treating the (N-[2-[4-(chlorosulfonyl)phenyl]ethyl]-5-methyl pyrazine-carboxamide] of the formula X with ammonia to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide of the formula I.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:38])=[CH:30][CH:31]=[C:26]4[C:25]([C:39]#[N:40])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:45])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:38])=[CH:30][CH:31]=[C:26]4[C:25]([C:39]([NH2:40])=[O:45])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(-c6ccccc6Cl)nc54)c3CO)ncc2c1
Reactant: CCO
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(-c6ccccc6Cl)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (4 mg, 6.92 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (29.7 μg, 0.0692 μmol, Eq: 0.01) were combined with Ethanol (853 μl) and Water (853 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h, then concentrated in vacuo. Mixture was diluted with acetonitrile and water and filtered. The resultant filtrate is lyophalized to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(2-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (3.9 mg, 95%, [M+H]+ 596).
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.OO.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C=C.FC(F)(F)C([O-])=[O:31].C([NH+](CC)CC)C>ClCCl>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:6]([OH:11])[CH2:7][OH:31]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CCCCCCCCCCBr
Reactant: O=C([O-])C(F)(F)F
Agent: CC[NH+](CC)CC
Agent: OO
Solvent: ClCCl
Product: OCC(O)CCCCCCCCCBr
Reaction time: 1 h

Procedure:
Trifluoroacetic anhydride (27.52 g, 0.139 moles) and hydrogen peroxide 30% (11.83 g, 0.348 moles) in dichloromethane (120 mls), were added to a stirred solution of 1-bromoundec-10-ene (24.50 g, 0.105 moles) and triethylammonium trifluoroacetate (11.38 g, 0.053 moles) in dichloromethane (125 mls). Stirring was continued for one hour after the addition was complete, after which time the solvent was evaporated. The residue was taken up into ether and washed with water and 2M sodium carbonate. The organics were then dried (MgSO4), filtered and evaporated. The solid was then triturated with 40-60 petrol and filtered to give the product as a white solid. (5.3 g, 20%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH3:31]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH2:30][CH3:31])[CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Reactant: CCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CCC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:24])[C:14]3[CH:21]=[C:20]([CH2:22]Cl)[O:19][C:15]=3[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:6][CH:5]=1.C(=O)(O)[O-:28].[Na+].O>CN(C=O)C>[Cl:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:24])[C:14]3[CH:21]=[C:20]([CH2:22][OH:28])[O:19][C:15]=3[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)oc21
Temperature: 25 °C

Procedure:
A solution of 2 N aq. sodium hydroxide (2.5 mL) was added to a solution of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]-pyridine-5-carboxamide (Example 2, 1.83 g) in DMF (40 mL). The mixture was heated and a sat. aq. sodium bicarbonate solution (10 mL) was added. The reaction mixture was allowed to cool to room temperature, was poured into water, and extracted with EtOAc (3×100 mL). The combined organic layers were concentrated. The crude product was purified by column chromatography (CH2Cl2/methanol, 100/1; 50/1; 20/1; 15/1) to afford 0.258 g of the title compound as a yellow solid. Physical characteristics. M.p. 229-230° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.63, 8.56, 7.42-7.32, 6.85, 5.53, 4.54, 4.51, 3.94; MS (EI) m/z 346 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH2:11][CH:12]([CH3:15])[CH2:13][OH:14].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:11][CH:12]([CH3:15])[CH2:13][OH:14])[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CC(N)CO
Solvent: O
Solvent: CS(C)=O
Product: CC(CO)Nc1ccc(C#N)cc1Cl
Reaction time: 2 h

Procedure:
4.00 g (25.7 mmol) 3-chloro-4-fluoro-benzonitrile are heated to 60° C. in 20 ml DMSO with 8.00 g (106.5 mmol) 2-amino-1-propanol with stirring for 2 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([NH:18][C:19]([C:21]2[S:35][C:24]3=[N:25][CH:26]=[C:27](C4C=NC=CC=4)[N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[CH3:40][N:41]([CH3:57])[C:42]1[N:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][N:43]=1>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([NH:18][C:19]([C:21]2[S:35][C:24]3=[N:25][CH:26]=[C:27]([C:45]4[CH:46]=[N:47][C:42]([N:41]([CH3:40])[CH3:57])=[N:43][CH:44]=4)[N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(-c3cccnc3)cnc2s1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(-c3cnc(N(C)C)nc3)cnc2s1
Yield: 13 %

Procedure:
Preparation analogous to the synthesis of 25h by using 2-dimethylamino-pyrimidine-5-boronic acid pinacol ester (1.5 eq). Purified by HPLC to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-(2-(dimethylamino)pyrimidin-5-yl)thieno[2,3-b]pyrazine-6-carboxamide 25k (4 mg, 13%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([NH:20][CH3:21])[N:3]=1.[CH3:22][I:23]>O1CCOCC1>[I-:23].[CH3:22][N+:3]1[C:4]([NH:20][CH3:21])=[CH:5][C:6]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:13]2)=[N:7][C:2]=1[CH3:1]
Reactant: CI
Reactant: CNc1cc(N2CCC(c3ccccc3)CC2)nc(C)n1
Solvent: C1COCCO1
Product: CNc1cc(N2CCC(c3ccccc3)CC2)nc(C)[n+]1C
Product: [I-]
Yield: 60 %

Procedure:
A mixture of 2-methyl-6-methylamino-4-(4-phenylpiperidino)pyrimidine (564 mg; 2 mM) and methyl iodide (1 ml; 16 mM) in dioxan (10 ml) was heated under reflux for 15 hours. The mixture was cooled, the solvent removed in vacuo and the residue was crystallised from a mixture of methanol and ether. There was thus obtained 1,2-dimethyl-6-methylamino-4-(4-phenylpiperidino)pyrimidinium iodide (506 mg, 60% yield) m.p. 193°-196° C.; microanalysis found: C,50.6; H,5.8; N,12.9%; C18H25N4I reqiures C,50.9; H,5.9; N,13.2%; NMR (200 MHz, d6 -DMSO): 1.45-1.75 (2H, octet, piperidine 3-H axial and 5-H axial), 1.85-2.00 (2H,d, piperidine 3-H equatorial and 5-H equatorial), 2.55-2.60 (3H,s, CH3), 2.85-2.95 (3H, d, NHCH3), 3.00-3.20 (3H, br, piperidine 2-H axial and 6-H axial), 3.45-3.55 (3H, s, N--CH3), 4.4-4.8 (2H, br, piperidine 2-H equatorial and 6-H equatorial), 5.8-5.85 (1H, s, pyrimidine 5-H), 7.15-7.40 (5H, complex, aromatic), 7.7-7.85 (1H,q, NH).
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:22]>>[ClH:22].[N+:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C@@H:9]1[CH2:10][S:7][C:6]([NH2:5])=[N:8]1)([O-:21])=[O:20]
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: NC1=N[C@H](Cc2cccc([N+](=O)[O-])c2)CS1
Temperature: 0 °C

Procedure:
1.1 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea in 12 cm3 of 6N hydrochloric acid are heated for 5 hours at a temperature in the region of 100° C. The reaction medium is then cooled to a temperature in the region of 0° C.; a white precipitate forms, which is filtered off on a sinter funnel and then washed with 3 times 20 cm3 of diethyl ether. The filter cake is then dried in a desiccator under vacuum. 0.68 g of (+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of beige-colored crystals melting at 232° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 3.15 (limiting AB: 2H); from 3.25 to 3.45 (mt: 1H); 3.63 (dd, J=13 and 8 Hz: 1H); 4.62 (mt: 1H); 7.68 (t, J=8 Hz: 1H); 7.81 (broad d, J=8 Hz: 1H); 8.18 (broad d, J=8 Hz: 1H); 8.24 (broad s: 1H); from 9.00 to 10.40 (unres. mult.: 3H); (αD20=+18.8±0.6 at a concentration of 0.5% in methanol)].
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)C=CC=CC=1.O>O1CCOCC1>[C:18]1([N:13]2[C:12]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(-c3ccccc3)c2CC1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
2,3-Diphenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a solution of the above compound (0.28 g) in 5 mL of 1,4-dioxane was added 0.29 g of K3PO4, 104.3 mg of phenylboronic acid and 43.0 mg of PdCl2dppf. The mixture was heated at 80° C. for 3 h. More phenylboronic acid (0.10 g) and PdCl2dppf (26 mg) were added and the temperature was increased to 100° C. After an additional 12 h, the mixture was poured into water (100 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were filtered through diatomaceous earth and the filtrate was concentrated in vacuo. Chromatography on SiO2 (0 to 20% EtOAc/hexanes) afforded 158.8 mg of the desired compound. MS (ESI): exact mass calculated for C24H27N3O2, 389.21. found, m/z 390.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.O=[C:42]1[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:43]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([N:23]([CH:33]3[CH2:34][CH2:35]3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:20]3=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]3[N:18]=2)=[CH:4][C:5]([C:14]#[N:15])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:42]2[CH2:43][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45]2)[CH2:10][CH2:9]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CN(C(=O)OC(C)(C)C)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 2-((2-chloro-5-cyano-3-(piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (500 mg, 0.901 mmol) in THF (2.5 mL) and MeOH (2.5 mL) was added tert-butyl 3-oxoazetidine-1-carboxylate (185 mg, 1.081 mmol), acetic acid (0.052 rnL, 0.901 mmol). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was cooled to 0° C., added sodium cyanoborohydride (113 mg, 1.802 mmol) and the reaction mixture was allowed to come to room temperature and stirred for 5 h at the same temperature. The solvent was removed completely under vacuum, the resultant residue was dissolved in ethyl acetate (100 ml), washed it with 10% NaHCO3 solution, brine, dried over anhydrous Na2SO4 and concentrated. The crude material was purified via ISCO (12 gm silica Redisep, 0 to 10% CH3OH—CHC13 gradient elution). The fractions were concentrated to get the tert-butyl 3-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperazin-1-yl)azetidine-1-carboxylate (500 mg) as a off white solid.