Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:24][C:23]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:15]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)c1cccc(-c2nc3ncccc3o2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2cccc(-c3nc4ncccc4o3)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
For amide formation, 3-(oxazolo[4,5-b]pyridin-2-yl)benzoic acid (30 mg, 0.125 mmol) was dissolved in 2 mL of DMF along with 3,4,5-trimethoxyaniline (23 mg, 1 eq) and 71 mg of HATU (1.5 eq). After 45 microliters of DIEA (2 eq) were added, the reaction mixture was stirred at room temperature for 18 hrs. It was then diluted with ethyl acetate and washed with water and concentrated. The resulting residue was purified by chromatography using a 9:1 mixture of CH2Cl2 to MeOH to afford 3-(oxazolo[4,5-b]pyridin-2-yl)-N-(3,4,5-trimethoxyphenyl)benzamide. (MS, M++H=406).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C[O:13][P:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([P:14]1(=[O:13])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1)=[O:5]
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: COP1Oc2ccccc2-c2ccccc21
Product: Cc1ccc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)c(C)c1
Temperature: 135 °C

Procedure:
33.7 g (0.2 mol) of 2,4-dimethylbenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 46 g (0.2 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise with stirring. The batch began to crystallize even during the addition. The temperature was then slowly increased to 135° C. with the proviso that toluene was added as diluent at 90° C. After digestion with toluene, 58 g (83% of theory) of the abovementioned compound of melting point 166° C. were obtained from the crystallizate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[NH2:27])=[O:5])[CH3:2].CC[O-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[N:8]=[C:7]1[NH2:27])=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)N=C(N)C(Cc2ccccc2)(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A solution of 37.4 g of 2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol is brought to the boil and treated with 17.1 g of benzyl bromide. After boiling for a further 60 minutes under reflux, the mixture is concentrated by distillation and the residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water. Concentration of the organic phase and recrystallization from ethanol gave 2-amino-3-benzyl-6-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 208° C (29.4 g, 63% of theory).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([NH:12][C:13]2[NH:17][CH2:16][CH2:15][N:14]=2)[C:4]([Br:11])=[C:5]2[N:10]=[CH:9][CH:8]=[N:7][C:6]=12.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH:20]=[CH:19]1>C(O)C>[Br:11][C:4]1[C:3]([N:12]2[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18](=[O:24])[N:17]3[CH2:16][CH2:15][N:14]=[C:13]23)=[CH:2][CH:1]=[C:6]2[C:5]=1[N:10]=[CH:9][CH:8]=[N:7]2
Reactant: Brc1c(NC2=NCCN2)ccc2nccnc12
Reactant: O=C1C=CC(=O)O1
Solvent: CCO
Product: O=C(O)C1CC(=O)N2CCN=C2N1c1ccc2nccnc2c1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 112.3 %

Procedure:
Brimonidine (7.0 g) and maleic anhydride (3.53 g) were added to ethanol free chloroform (200 ml) and heated to 50° C. overnight. The solvent was evaporated and the residue slurried in MeCN (50 ml) at 30° C. for 2 h. The resultant solid was filtered washed with MeCN (25 ml) and dried in an oven at 40° C. to yield 10.5 g of 8-(5-bromoquinoxalin-6-yl)-5-oxo-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 48.8 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridinehydrochloride (step 1 example 103) (50 mg. 0.077 mmol) was alkylated using (S)-2-methyloxirane (9 mg, 0.155 mmol), DIPEA (29 mg, 0.231 mmol) and ethanol (2 mL) to get 25 mg (9.8% yield) of the titled compound. MS: m/z=664.8 (M+1).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Reactant: Clc1cccc(CBr)c1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(Cl)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 using 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole and using 3-chlorobenzyl bromide instead of benzyl bromide.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[C:22]1([CH:28]([CH3:31])[CH:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H][H]>>[C:22]1([CH:28]([CH3:31])[CH2:29][OH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: CC(C=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(CO)c1ccccc1
Yield: 58.3 %

Procedure:
Into a stainless steel autoclave equipped with a glass inner tube, Cu(NO3)(PPh3)2 (11.7 mg, 0.018 mmol) and triphenylphosphine (28.3 mg, 0.108 mmol) were introduced. The inside of the autoclave was then replaced with nitrogen. To the autoclave, an ethanolic solution of sodium hydroxide (0.03 M) (6.0 mL, 0.18 mmol) and 2-phenylpropionaldehyde (1.21 mL, 9 mmol) were added, and stirring was performed at a hydrogen pressure of 5 MPa at 50° C. for 16 hours. The hydrogen was released with great care, and the conversion was analyzed by GC (95%). The contents were concentrated, and then purified by silica gel chromatography. Thus, 715 mg of 2-phenyl-1-propanol was obtained (yield: 58%).
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[C@@H:6]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].CO.C(OC(C)(C)C)=O>O1CCCC1>[C:21]([O:20][C:18](=[O:19])[NH:17][C@H:6]([CH2:5][OH:4])[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@H](CS(=O)(=O)c1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)CS(=O)(=O)c1ccccc1

Procedure:
To a solution of lithium borohydride in tetrahydrofuran (2M, 1.14 ml, 2.28 mmol) was added slowly at 0° C. a solution of (R)-3-benzenesulfonyl-2-tert-butoxycarbonylamino-propionic acid methyl ester (0.52 g, 1.51 mmol) in tetrahydrofuran (3 ml). After stirring at room temperature for 2.5 hours methanol was added (0.5 ml). The mixture was partitioned between ethyl acetate and saturated ammoniumchloride solution. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1 to yield a white solid, (0.292 g, 61%); MS (ISP): 316.0 ((M+H)+/); 216.1 ((M+H—BOC)+.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=4)[N:21]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: OC1(c2ccc(F)cc2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 74 %

Procedure:
A mixture of 4-(4-fluorophenyl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-(4-fluorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 74% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15](Br)[N:16]3[CH2:19][CH3:20])=[C:12]([NH2:22])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:25]([OH:27])[CH3:26]>>[C:1]1([CH2:7][CH2:8][O:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([O:27][CH2:25][CH3:26])[N:16]3[CH2:19][CH3:20])=[C:12]([NH2:22])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCn1c(Br)nc2c(N)nc(OCCc3ccccc3)nc21
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOc1nc2c(N)nc(OCCc3ccccc3)nc2n1CC
Temperature: 85 °C
Yield: 52 %

Procedure:
To a suspension of 2-(2-phenylethoxy)-8-bromo-9-ethyl-9H-purin-6-ylamine (145 mg, 0.4 mmol) and dry NaOH (80 mg, 2.0 mmol) was added ethanol (25 mL). This mixture was heated at 85° C. for 7 hours. The solvent was removed under reduced pressure and the residue was neutralized with 2N HCl and extracted with CHCl3. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from acetonitrile to give 2-(2-phenylethoxy)-8-ethoxy-9-ethyl-9H-purin-6-ylamine (68 mg, 52%) as a white solid: mp 161–164° C.; 1H NMR (Me2SO-d6) δ 1.26 (t, 3H, J=7.1 Hz, OCH2CH3), 1.33 (t, 3H, J=7.0 Hz, NCH2CH3), 3.00 (t, 2H, J=6.9 Hz, CH2CH2Ph), 3.88 (q, 2H, J=7.1 Hz, OCH2CH3), 4.38 (t, 2H, J=6.9 Hz, CH2CH2Ph), 4.48 (q, 2H, J=7.0 Hz, NCH2CH3), 6.79 (s, 2H, NH2), 7.18–7.36 (m, 5H, H-Ph). Anal. (C17H21N5O2) C, H, N.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCN(CCC(=O)O)C4)no2)cc1C#N
Temperature: 60 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
Ethyl 3-[9-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]propanoate (Preparation 92) (40 mg, 0.084 mmol) was dissolved in ethanol (5 ml). 2M sodium hydroxide (0.210 ml, 0.420 mmol) was added and the reaction mixture stirred at 60° C. for 4 hours. The solvent was evaporated, then the reaction mixture was diluted with water, neutralised with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to give the product as a colourless solid (16 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1.[CH2:20]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([O:24][C:25](=[O:30])[C:26]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:28])[CH3:27])[CH2:21][CH2:22][CH3:23]
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(O)ccc2n1C
Reactant: CCCCOC(=O)C(C)(C)Br
Product: CCCCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(Cl)cc1)c(C)n2C

Procedure:
The above compound was prepared from 3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid butylester, using a procedure analogous to that of Example 102.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])#[CH:36]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2].[Cu]I.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:36]#[C:35][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:5]=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cc(I)ccn1
Agent: [Cu]I
Agent: [Pd+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
2-Chloro-4-iodo-pyridine (10 g, 42 mmol), palladium bis(triphenylphosphine)dichloride (2.93 g, 4.18 mmol) and triphenylphosphine (1.09 g, 4.17 mmol) are dissolved in de-gased dry THF (10 mL) and triethylamine (42 mL, 301 mmol). The resulting mixture is stirred for 1 hr at room temperature. Then Copper (I) iodide (2.3 g, 12 mmol) and ethynyl-trimethyl-silane (7.1 mL, 50 mmol) are added. The reaction mixture is stirred for 12 hrs at room temperature. The solvents are removed and the residue is diluted with water (100 mL). The mixture is extracted with EtOAc (3×250 mL) and the organic layers are combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product. Purification by silica flash column chromatography using 0.5% EtOAc in hexanes affords 4.6 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[C:4]([CH3:19])[CH:3]=1.[F:20][C:21]([F:27])([F:26])[S:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CCCCC.C(OCC)(=O)C>[CH3:14][N:13]1[C:9]([O:8][C:6]2[CH:5]=[C:4]([CH3:19])[CH:3]=[C:2]([O:1][CH2:24][CH2:23][S:22][C:21]([F:27])([F:26])[F:20])[N:7]=2)=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]1
Reactant: OCCSC(F)(F)F
Reactant: Cc1cc(O)nc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: Cc1cc(OCCSC(F)(F)F)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.7 %

Procedure:
A mixture of 1A (0.55 g), 2-(trifluoromethylthio)-ethanol (0.35 g, Example A), triphenylphosphine (0.64 g) and diethyl azodicarboxylate (0.42 g) in dry tetrahydrofuran (5 ml) is stirred for 20 hours at ambient temperature. The reaction mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 9/1 v/v) yields 0.45 g of the title compound as an colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:6]2[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[C:21]([OH:24])(=[O:23])[CH3:22]>C([O-])(=O)C.[Ag+]>[CH:16]1([N:13]2[C:6]3[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=3[CH:4]=[C:3]([CH2:2][O:24][C:21](=[O:23])[CH3:22])[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)O
Reactant: CSc1ncc2cc(CBr)c(=O)n(C3CCCC3)c2n1
Agent: [Ag+]
Agent: CC(=O)[O-]
Product: CSc1ncc2cc(COC(C)=O)c(=O)n(C3CCCC3)c2n1
Temperature: 110 °C
Yield: 71 %

Procedure:
6-Bromomethyl-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.33 g, 3.75 mmol), prepared as in Example 25, and silver acetate (1.03 g, 6.2 mmol) were added to glacial acetic acid (10 ml) and heated to 110° C. for 5 hours. The solvents then were evaporated at reduced pressure and the resulting residue was suspended in ethyl acetate and filtered. The solid obtained was recrystallized from ethyl acetate to provide acetic acid 8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl ester as a solid (0.89 g, 71%). MS (APCI) M++1; Calc'd 334.11. Found 334.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[NH:8][C:7]2=O.CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(Cl)cccc12
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Cl)c3n2)nc1
Temperature: 115 °C
Yield: 111 %

Procedure:
To 8-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4(3H)-one (250 mg, 0.77 mmol) were added DIEA (0.28 mL, 1.53 mmol) and phosphorous oxychloride (5.3 mL, 57 mmol), and the mixture was heated at 115° C. for 6 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. Toluene was added and evaporated twice, and the residue was partitioned between EtOAc (20 mL) and cold saturated aq NaHCO3 (10 mL). The separated EtOAc layer was diluted with EtOAc (60 mL) and washed with saturated aq NaHCO3 (10 mL) and brine (2×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 4,8-dichloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline as a brown viscous oil (294 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[C:19]([CH2:21][C:22]1([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[C:19]([CH2:21][C:22]1([N:33]2[CH:37]=[C:36]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=34)[CH:35]=[N:34]2)[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)#[N:20]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 104.8 %

Procedure:
A mixture of 4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.0 g, 3.0 mmol), tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (1.2 g, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.2 mmol) and cesium carbonate (3.0 g, 9.2 mmol) in 1,4-dioxane (6 mL) and water (0.9 mL) was degassed and sealed. It was stirred at 90° C. for 2 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-50%) to afford the desired product (1.6 g). LCMS (M+H)+: m/z=509.3.
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:20])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[CH:16][O:15][C:14]=1[CH3:19])=[CH:3]\[C:4](Cl)=[O:5].[O-:21]CC.[Na+:24]>CO>[CH3:1]/[C:2](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:20])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[CH:16][O:15][C:14]=1[CH3:19])=[CH:3]\[C:4]([O-:21])=[O:5].[Na+:24]
Reactant: CC[O-]
Reactant: CC(/C=C/c1c(C)coc1C)=C\C=C\C(C)=C\C(=O)Cl
Agent: [Na+]
Solvent: CO
Product: CC(/C=C/c1c(C)coc1C)=C\C=C\C(C)=C\C(=O)[O-]

Procedure:
(E,E,E,E)-3,7-dimethyl-9-(2,4-dimethyl-3-furyl)-2,4,6,8-nonatetraenoic acid chloride (1.5 g.) was dissolved in a solution of methanol and sodium ethoxide (0.3 g.) and the resulting mixture was then concentrated to dryness to give sodium (E,E,E,E)-3,7-dimethyl-9-(2,4-dimethyl-3-furyl)-2,4,6,8-nonatetraenoate m.p.~280° with decomposition as an amorphous solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=[CH:7][CH:6]=1)=[N+]=[N-]>C(O)C.[Pt]>[NH2:1][CH2:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1cccc(N2CCCC2=O)n1
Agent: [Pt]
Solvent: CCO
Product: NCc1cccc(N2CCCC2=O)n1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
A solution of crude 1-(6-azidomethyl-pyridin-2-yl)pyrrolidin-2-one (containing triphenylphosphine oxide), in ethanol (100 mL) was treated with platinum (5% on carbon), stirred under hydrogen at 45° C. and ambient pressure for 18 h, filtered through a pad of Celite, concentrated in vacuo then co-evaporated with toluene and then chloroform to give the title compound (11.32 g) as a white solid, contaminated with triphenylphosphine oxide; LC-MS retention time 0.66 min, (M+H)+ 192.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1ccncc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
20.3 g of p-nitrophenyl chloroformate were dissolved in 150 ml of CH2Cl2 (absolute) and the solution was cooled to 0° C. under N2. 520 mg of 4-dimethylaminopyridine (DMAP) were added and 10 g of 4-hydroxymethylpyridine in 50 ml of CH2Cl2 (absolute) were then added dropwise to this solution. The mixture was stirred overnight at R.T. and the crystals which had precipitated were filtered off. The crystals were recrystallized using fresh CH2Cl2 under the influence of heat and, after cooling, were filtered off again.