Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][CH:34]=1)[C:8]([NH:10][CH:11]([C:13]1[N:18]=[N:17][C:16]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[N:15][CH:14]=1)[CH3:12])=O)(=O)C.P(Cl)(Cl)(Cl)=O.Cl.[OH-].[Na+]>ClCCCl.CO>[NH2:4][C:5]1[CH:6]=[C:7]([C:8]2[N:18]3[C:13]([CH:14]=[N:15][C:16]([NH:19][C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=4)=[N:17]3)=[C:11]([CH3:12])[N:10]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(NC(C)=O)c3)nn2)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(N)c4)n3n2)cc(OC)c1OC
Temperature: 25 °C
Yield: 2.1 %

Procedure:
To a solution of 3-(acetylamino)-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 32) (110 mg, 0.24 mmol) in 1,2-dichloroethane (10 mL) was added phosphorous oxychloride (0.175 mL, 1.9 mmol). The mixture was refluxed for 6 hours, cooled to room temperature and more phosphorous oxychloride (0.10 mL, 1.0 mmol) was added. The reaction was then refluxed for 4 hours. After cooling to room temperature the reaction was diluted with methanol, then poured onto a mixture of ice and concentrated HCl. This mixture was brought to a pH of 8 by addition of concentrated aqueous NaOH. The mixture was then extracted with ethyl acetate, concentrated under vacuum and purified by reverse-phase HPLC to give 7-(3-aminophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (2 mg) as a yellow solid. 1H NMR (CD3OD): δ9.00 (s, 1H), 7.60 (d, J=7.87 Hz, 1H), 7.54 (s, 1H), 7.21 (t, J=7.78 Hz, 1H), 7.09 (s, 2H), 6.79 (dd, J=7.87 and 2.01 Hz, 1H), 3.77 (s, 6H), 3.73 (s, 3H), 2.56 (s, 3H). MS m/z 406 (M+1).
Reaction SMILES: [Cl-].[CH:2](=[N:9][N+:10]1[CH:14]=[CH:13][N:12](N=CC2C=CC=CC=2)[C:11]=1[CH3:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C-]#N.[K+]>CO.O>[CH:2](=[N:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH3:23])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1n(N=Cc2ccccc2)cc[n+]1N=Cc1ccccc1
Agent: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nccn1N=Cc1ccccc1
Reaction time: 0.25 h

Procedure:
3.24 g of 1,3-bis(benzylideneamino)-2-methylimidazolium chloride are dissolved in 50 ml of methanol. The solution is cooled to 0° (internal temperature) and treated while stirring with a solution of 2.6 g of potassium cyanide in 8 ml of water, whereby the temperature is not allowed to rise substantially. After 15 minutes, the methanol is removed by evaporation in a vacuum at the lowest possible temperature. The residue is diluted with 30 ml of water, whereupon the mixture is extracted three times with chloroform. The dried chloroform extract is evaporated and there is obtained 1-benzylideneamino-2-methylimidazole of m.p. 125°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:15]([NH2:21])[CH:16]1[O:20][CH2:19][CH2:18][CH2:17]1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][O:20]3)[N:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(-c2ccnc(Cl)n2)ccn1
Reactant: NCC1CCCO1
Product: Clc1cc(-c2ccnc(NCC3CCCO3)n2)ccn1

Procedure:
The title compound was prepared from 2-chloro-4-(2-chloro-4-pyridinyl)pyrimidine (i.e., the product of Example 6, Step A) and tetrahydrofurfurylamine in the same fashion as described in Example 9, Step A, m.p. 74-75° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]2[S:25][CH:24]=[N:23][CH:22]=2)[CH:20]=1)[NH2:17].[F:26][C:27]([F:32])([F:31])[C:28]([CH3:30])=[O:29]>C1COCC1.O.C(Cl)Cl>[NH2:17][C:16]1[CH:18]=[C:19]([C:21]2[S:25][C:24]([C:28]([OH:29])([CH3:30])[C:27]([F:32])([F:31])[F:26])=[N:23][CH:22]=2)[CH:20]=[C:14]([CH3:13])[CH:15]=1
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Reactant: CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: O
Product: Cc1cc(N)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To diisopropylamine (18.73 ml, 131 mmol) in THF (263 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 54.7 ml, 137 mmol). The reaction was aged for 30 minutes at −40° C. before cooling to −78° C. Intermediate 16 (10 g, 52.6 mmol) was added as a solution in 5 mL THF at −78° C. and was then warmed to 0° C. over 2 hours. The reaction was once again cooled to −78° C. before adding 1,1,1-trifluoroacetone (14.85 mL, 158 mmol) as a solution in 5 mL THF at −78° C. The reaction was allowed to warm to room temperature slowly, and was diluted with water and DCM. The layers were separated and the organic layer was dried over sodium sulfate and was concentrated in vacuo. The resultant residue was purified on silica gel (0-30% ethyl acetate in hexanes) to yield a yellow oil which solidified in hexanes overnight. The yellow to off-white solid was sonicated and filtered to yield 2-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,1,1-trifluoropropan-2-ol (11.69 g, 38.7 mmol, 73.6%). MS APCI: [M+H]+ m/z 303.0. 1H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 6.76 (s, 1H), 6.67 (s, 1H), 6.52 (s, 1H), 4.53 (br s, 2H), 2.29 (s, 3H), 1.83 (s, 3H).
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].Br[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][CH:10]=[CH:9]2>C(#N)C.CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:15]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[CH:1]=[O:3]
Reactant: Fc1cc2ncccc2cc1Br
Reactant: O=C[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: CS(C)=O
Product: O=Cc1cc2cccnc2cc1F
Temperature: 120 °C
Yield: 10.4 %

Procedure:
To a suspension of Pd(PPh3)4 (1.27 g, 1.1 mmol) and sodium formate (13.8 g, 132 mmol, 6 eq.) in acetonitrile (30 mL) was added a solution of 6-bromo-7-fluoro quinoline (5 g, 22 mmol) in DMSO (30 mL). The reaction mixture was heated at 120° C. under a CO atmosphere (1 MPa) for 4 h, cooled to it and concentrated under reduced pressure. The residue was partitioned between water (100 mL) and EtOAc (150 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by column choromatography with gradient petroleum:EtOAc from 10:1 to 3:1 to give the title compound as a white solid (400 mg, 10.4%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.95 (s, 1H), 8.46 (m, 1H), 8.20 (m, 1H), 7.75 (d, 1H), 7.53 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:13]([Cl:14])=[CH:12][N:11]([CH3:15])[C:10]=1[C:16]([O:18]CC)=O.P(=O)(O)(O)O.N>>[Cl:14][C:13]1[C:9]2[NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:16](=[O:18])[C:10]=2[N:11]([CH3:15])[CH:12]=1
Reactant: CCOC(=O)c1c(Nc2ccccc2N)c(Cl)cn1C
Agent: N
Agent: O=P(O)(O)O
Product: Cn1cc(Cl)c2c1C(=O)Nc1ccccc1N2
Temperature: 110 °C

Procedure:
A mixture of ethyl 3-[(2-aminophenyl)amino]-4-chloro-1-methyl-1H-pyrrole-2-carboxylate (27.4 g, 0.0933 mol) and 85% phosphoric acid (90 ml) is heated to 110° C. under water jet vacuum for 2 hours with stirring. While still hot, the reaction mixture is then stirred into ice water (1 liter) and adjusted to pH 6 with aqueous ammonia solution. The solid obtained (23.0 g) melted at 172°-175° C. after recrystallisation from acetonitrile.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=O)[CH2:2][CH2:3][CH3:4].COC1C=CC(C2(C3C=CC(OC)=CC=3)CC[NH:28]CC2)=CC=1.N>>[NH2:28][C:1]([CH2:2][CH2:3][CH3:4])=[CH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: CCCC(=O)CC(=O)OCc1ccccc1
Reactant: COc1ccc(C2(c3ccc(OC)cc3)CCNCC2)cc1
Agent: N
Product: CCCC(N)=CC(=O)OCc1ccccc1

Procedure:
A mixture of benzyl butyrylacetate (22.0 g, 0.10 mol) and 10 g of 4 A molecular sieves was treated with ammonia gas which was bubbled through the mixture for 38 hrs at 50° C. After filtration, benzyl 3-amino-2-hexenoate was obtained as a yellowish oil (21 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.C(N(CC)CC)C.[Cl:38][C:39]1[C:44]([NH:45][C:46]2[N:51]=[C:50]([N:52]([CH:62]3[CH2:64][CH2:63]3)[CH2:53][C:54]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=3)[C:49]3=[N:65][CH:66]=[C:67]([C:68]#[N:69])[N:48]3[N:47]=2)=[CH:43][C:42]([C:70]#[N:71])=[CH:41][C:40]=1[N:72]1[CH2:77][CH2:76][C@@H:75]([NH:78][C:79](=[O:82])[O:80][CH3:81])[C@H:74](O)[CH2:73]1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][C@@H:76]1[C@@H:75]([NH:78][C:79]([O:80][CH3:81])=[O:82])[CH2:74][CH2:73][N:72]([C:40]2[CH:41]=[C:42]([C:70]#[N:71])[CH:43]=[C:44]([NH:45][C:46]3[N:51]=[C:50]([N:52]([CH:62]4[CH2:64][CH2:63]4)[CH2:53][C:54]4[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=4)[C:49]4=[N:65][CH:66]=[C:67]([C:68]#[N:69])[N:48]4[N:47]=3)[C:39]=2[Cl:38])[CH2:77]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H]1CCN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@@H]1OC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (30.4 mg, 0.140 mmol), Tetramethylfluoroformamidinium hexafluorophosphate (37.0 mg, 0.140 mmol) and triethyl amine (0.039 mL, 0.280 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 h. (+/−)-methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (Example 171, 18 mg, 0.028 mmol) and DMAP (0.342 mg, 2.80 μmol) were added and the reaction solution was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 5-30% ethyl acetate/dichloromethane). (+/−)-(R)-(3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (23 mg) was obtained as a colorless oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:18][N:17]=2)[CH:10]=1)(=O)=O.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]1>CN(C=O)C>[F:31][CH:29]([F:30])[O:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:20]=[N:21][C:16]([NH:15][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][N:32]3[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]3)=[N:17][CH:18]=2)=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)OCCOc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCOc2cccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)c2)CC1
Temperature: 95 °C

Procedure:
2-(3-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl methanesulfonate 40b (0.4 mmol), ethyl piperidine-4-carboxylate (0.9 mmol) are dissolved in DMF (3 mL) and heated to 95° C. for 6 h then cooled to rt. The reaction mixture is partitioned with EtOAC and water. The organic layer is washed with water, brine, dried over magnesium sulfate, filtered, and reduced to dryness. The crude product is triturated with MeOH and filtered to yield ethyl 1-(2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate 41 as white solid. MS (m/z) (M+1)+: 513.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]3)=[N:9][C:10]=2[C:11]2[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([F:29])[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:36](O)(=[O:39])[CH:37]=[CH2:38]>>[C:36]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@H:30]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([F:29])[CH:12]=2)[N:9]=1)(=[O:39])[CH:37]=[CH2:38]
Reactant: CCCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCCN4)n4ccnc(N)c34)cc2F)c1
Reactant: C=CC(=O)O
Product: C=CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cc(CCC)ccn3)c(F)c2)c2c(N)nccn12
Yield: 28.9 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluoro-N-(4-propylpyridin-2-yl)benzamide (intermediate 39) and acrylic acid, to afford the title compound (5.9 mg, 28.9%). Data: UPLC(C) Rt: 2.41 min; m/z 528.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH2:8][NH:9][C@H:10]([CH3:27])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]#[N:22])[CH:20]=1)[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:16][CH2:15]2)[CH3:2].[OH-].[Na+].OO.S([O-])([O-])=[O:37].[Na+].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH2:8][NH:9][C@H:10]([CH3:27])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([NH2:22])=[O:37])[CH:20]=1)[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:16][CH2:15]2)[CH3:2]
Reactant: CCOc1ccccc1OCCN[C@H](C)Cc1cc(C#N)c2c(c1)CCN2CCCO
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1ccccc1OCCN[C@H](C)Cc1cc2c(c(C(N)=O)c1)N(CCCO)CC2
Temperature: 27.5 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
(R)-5-[2-[[2-(2-Ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carbonitrile (5.95 g) was dissolved in dimethylsulfoxide (16.4 ml), and 5N sodium hydroxide solution (0.25 ml) was added to the solution. To the mixture was added 30% hydrogen peroxide (1.55 ml) keeping inner temperature below 25° C., and the mixture was stirred overnight at an inner temperature of 25-30° C. A solution of sodium sulfite (2.39 g) in distilled water (82 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, distilled water and brine subsequently, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, the residue was recrystallized from ethyl acetate to give (R)-5-[2-[[2-(2-ethoxyphenoxy)-ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carboxamide (4.72 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][C@H:38]1[CH2:37][CH2:36][C@@H:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c7) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=3)=[O:22])=[C:16]([C:38]3[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][CH:39]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47].CO>C(Cl)Cl.CO>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[CH3:44][C:41]1([CH3:45])[CH2:42][CH2:43][C:38]([C:16]2[N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])=[CH:39][CH2:40]1
Reactant: CC1(C)CC=C(c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2nc(C3CCNCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 97 %

Procedure:
A solution of 215 mg (0.339 mmol) 5-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL of CH2Cl2 was treated with three drops MeOH and 3 mL TFA at room temperature for 4 h. MeOH (10 mL) was added and the solvents evaporated in vacuo. Chromatography of the residue on a 50-g silica Varian MegaBond Elut column with 10% MeOH—CH2Cl2 afforded 210 mg (97%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.59 (d, 1H, J=8.4 Hz), 8.04 (s, 1H), 7.28 (d, 1H, J=8.4 Hz), 6.02-5.93 (m, 1H), 3.58-3.48 (m, 2H), 3.32-3.03 (m, 3H), 2.54-2.42 (m, 2H), 2.23-2.02 (m, 6H), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C23H28N6O, 405.2 (M+H), found 405.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.O1CCCC1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OCC1(CO)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCC1(COCc2ccccc2)CCC1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 8.0 g (69 mmol) of [1-(hydroxymethyl)cyclobutyl]methanol in 120 ml of a 1:1 mixture of tetrahydrofuran:N,N-dimethylformamide was added 3.30 g (69 mmol) of a 60% dispersion of sodium hydride in oil and the contents stirred for 30 min. 8.6 mL (72.4 mmol) of benzyl bromide was then added and the contents stirred for 2 h. The reaction was quenched with aqueous ammonium chloride followed by the addition of diethyl ether. The organic phase was isolated, dried using magnesium sulfate, and concentrated under vacuum to afford the crude product which was purified by silica gel chromatography using ethyl acetate:hexane (3:7) as the eluent to afford 12.0 g (86%) of {1-[(benzyloxy)methyl]cyclobutyl}methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.25 (m, 5H), 4.49 (s, 2H), 3.66 (d, J=6 Hz, 2H), 3.52 (s, 2H), 2.53 (t, J=6 Hz, 1H), 1.91-1.73 (m, 6H). GC-MS m/z 207 (M+H).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[CH:21]=[CH:20][C:19]4[C:23]5[N:27]=[CH:26][NH:25][C:24]=5[CH:28]=[CH:29][C:18]=4[C:17]=3[N:16]=[CH:15][N:14]=2)[CH:10]=[CH:11][CH:12]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[CH:21]=[CH:20][C:19]4[C:23]5[N:27]=[CH:26][NH:25][C:24]=5[CH:28]=[CH:29][C:18]=4[C:17]=3[N:16]=[CH:15][N:14]=2)[CH:10]=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2ncnc3c2ccc2c3ccc3[nH]cnc32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(-c2ncnc3c2ccc2c3ccc3[nH]cnc32)c1

Procedure:
A slurry of 2.00 g (5.12 mmoles) of 6-(m-trimethylsilylethynylphenyl)benzimidazoquinazoline and 200 mg of anhydrous potassium carbonate in 100 ml of anhydrous methanol was stirred at 25° for 3 hours. The solvent was removed and the residue was dissolved in 100 ml of chloroform, washed with 100 ml of 5% hydrochloric acid and then with 100 ml of water. The organic phase was dried over magnesium sulfate and concentrated to give a yellow solid which was recrystallized from ether-hexane. Yield: 1.55 g (4.86 mmoles, 94.9%): ir (KBr) 3300 cm-1 (medium, sharp, C≃C--H); mass spectrum (70 ev) m/e 319 (molecular ion).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.Cl[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]1)[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:12]2[C:11]([CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:28][CH2:27]3)=[N:10][C:9]3[C:13]2=[N:14][CH:15]=[N:16][C:8]=3[O:2][CH3:1])=[CH:19][CH:20]=1
Reactant: C[O-]
Reactant: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3c(Cl)ncnc32)cc1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1ncnc2c1nc(CC1CCN(Cc3ccccc3)CC1)n2Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a previously prepared sodium methoxide solution, starting from 25 parts of sodium in 400 parts of methanol, were added 49.4 parts of 6-chloro-9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-9H-purine. After stirring for 8 hours at reflux temperature, the reaction mixture was cooled and 1000 parts of water were added. The precipitated product was filtered off and dried, yielding 34.5 parts (70.4%) of 9-[(4-fluorophenyl)methyl]-6-methoxy-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-9H-purine (compound 184).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:22]4[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Reactant: OC1CCNC1
Product: OC1CCN(CC(O)COc2ccc(-c3nc4cc(Br)cnc4[nH]3)cc2)C1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(oxiran-2-ylmethoxy)phenyl]-3H-imidazo[4,5-b]pyridine and pyrrolidin-3-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>O.C(=S)=S>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:19](=[O:21])[CH3:20])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: COc1ccc(-c2ccccc2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 4′-methoxybiphenyl (0.05 mol) and AlCl3 (0.06 mol) were dissolved in boiling CS2 (60 mL) with stirring. Acetyl chloride (0.1 mol) was added dropwise and reflux continued for 1 hour. The mixture was poured onto crushed ice (150 mL) containing water (50 mL) and HCl (50 mL). The organic phase was separated and the CS2 removed by distillation. The residue was recrystallised from aqueous isopropanol to give the title compound. δC (CDCl3, 62.9 MHz): 26.6, 55.4, 114.4, 126.6, 128.4, 129.0, 132.2, 135.3, 145.4, 159.9 and 198.0