Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][CH:14]=[C:10]3[CH:11]=[CH:12][CH:13]=[C:9]3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]1([C:7]2([CH2:16][C:17]([O:19][CH3:22])=[O:18])[CH2:15][CH:14]=[C:10]3[CH:11]=[CH:12][CH:13]=[C:9]3[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC1(c2ccccc2)CC=C2C=CC=C2O1
Solvent: O
Solvent: CO
Product: COC(=O)CC1(c2ccccc2)CC=C2C=CC=C2O1
Yield: 228.2 %

Procedure:
A solution of 20.45 g of the product of Step B, 200 ml of methanol and 6 g of p-toluene sulfonic acid was refluxed for one hour and the solution was brought to dryness, then poured into water. Extraction was carried out with methylene chloride and the extracts were dried, filtered and concentrated to obtain 21.33 g of the desired product with a Rf =0.33 (eluant: hexane - methylene chloride (60-40)).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:26]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:28])[CH3:27]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 48.7 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 4. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with acetyl chloride (0.012 mL, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.030 g of a white solid.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH3:10])=[CH:3][CH:2]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]1([CH3:27])[CH:2]=[CH:3][C:4]([CH:7]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH3:10])[C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(N[C@H](C)c2cccc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(N[C@H](C)c2cccc(F)c2)c2cccc(N)c2)cc1

Procedure:
Following a procedure similar to that described in Example (59b), 3.59 g of N-[(p-tolyl)-(3-nitrophenyl)methyl]-N-[(R)-1-(3-fluorophenyl)ethyl]amine [prepared as described in step (a) above], 4.68 g of nickel chloride hexahydrate and 1.49 g of sodium borohydride were reacted, separated and purified, to obtain 955 mg of isomer A and 649 mg of isomer B of the title compound, each as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[O:22]([CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]Cl)[CH2:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:38][CH2:37][CH2:36][N:33]1[CH2:32][CH2:31][CH:30]([CH2:29][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:35][CH2:34]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: ClCCCN1CCC(COc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2c1ncn2CCCN1CCC(COc2ccccc2)CC1
Temperature: 40 °C
Yield: 42 %

Procedure:
A mixture of 15.4 g (0.1 mole) of 6-chloropurine, 75 ml of N,N-dimethyl formamide, 13.8 g (0.1 mole) of potassium carbonate and 26.8 g (0.1 mole) of 3-(4-phenoxymethylpiperidino)-propyl chloride is heated to 40° C for 6 hours, while stirring. The reaction mixture is then mixed with water extracted with ethyl acetate and the extract is dried and evaporated. The residue obtained is recrystallized from ethyl acetate/ligroin. There are obtained 16.2 g (42% of theory) of 6-chloro-9-[3-(4-phenoxymethylpiperidino)-propyl]-purine; m.p. 95° - 96° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=O.[CH3:13][C:14]1[CH:15]=[C:16]([NH2:29])[CH:17]=[N:18][C:19]=1[N:20]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[N:21]1>C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[C:16]([N:29]=[CH:1][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=2)[CH:17]=[N:18][C:19]=1[N:20]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[N:21]1
Reactant: Cc1cc(N)cnc1-n1cc(C(F)(F)F)cn1
Reactant: COC(=O)c1ccc(C=O)nc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C=Nc2cnc(-n3cc(C(F)(F)F)cn3)c(C)c2)nc1
Yield: 100 %

Procedure:
A mixture of methyl 6-formylnicotinate (251.3 mg, 1.52 mmol) and 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine (369 mg, 1.52 mmol) in toluene (8 mL) was heated at reflux under nitrogen overnight. The reaction mixture was concentrated to give methyl 6-((5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylimino)methyl)nicotinate (592 mg, 100%). 1H NMR (400 MHz, (CD3)2SO, δ): 9.09 (d, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 8.35-8.30 (m, 2H), 8.20-8.17 (m, 1H), 8.11 (s, 1H), 7.90 (d, 1H), 3.79 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][C:16]1=[O:21])([CH3:14])[C@@H:12]([C:22]([OH:24])=[O:23])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)O.O.[CH2:31]([OH:33])[CH3:32]>>[CH2:31]([O:33][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C:16](=[O:21])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([OH:24])=[O:23])[CH2:4][C@@H:3]1[OH:1])[CH3:32]
Reactant: CCO
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Agent: O=S(=O)(O)O
Solvent: O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
A solution of 2α,3α-epoxy-5α-androstan-11-one-17β-carboxylic acid (940 mg.) and concentrated sulphuric acid (0.25 ml.) in dry ethanol (30 ml.) was stirred at room temperature for 30 minutes. Water (100 ml.) was added and the reaction mixture extracted with chloroform. The chloroform solution was washed with water, dried, filtered and evaporated to give a froth which solidified when triturated with chloroform/petrol. Filtration afforded the solid crude product (752 mg.) which, after recrystallisation from ethanol/water, afforded the pure title compound; m.p. 249°-260°; [α]D + 74°, (c 0.33).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]([C:21]2[CH:22]=[C:23]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=2)[C:10]=1[CH2:32][CH2:33]Cl>>[CH3:31][NH:30][S:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:11]2[C:10]3[CH2:32][CH2:33][N:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)[C:9]=3[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:12]=2)[CH:22]=1)(=[O:29])=[O:28]
Reactant: Nc1ccncc1
Reactant: CNS(=O)(=O)c1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: CNS(=O)(=O)c1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1

Procedure:
Using 4-aminopyridine instead of 3-aminopyridine, and 3-[6-chloro-5-(2-chloro-ethyl)-2-morpholin-4-yl-pyrimidin-4-yl]-N-methyl-benzenesulfonamide instead of 4-[4-chloro-5-(2-chloro-ethyl)-6-phenyl-pyrimidin-2-yl]-morpholine, in the same manner as Example 1-A-37, the desired compound was obtained as a yellow solid (yield 9%).
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.BrC1C=C2C(CC3C=CC(NCC4C=CC(Cl)=CC=4)=NC=3)=CNC2=NC=1.[N:54]1([CH2:60][CH2:61][O:62][C:63]2[CH:64]=[C:65]3[CH:71]=[CH:70][NH:69][C:66]3=[N:67][CH:68]=2)[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.N1C2C(=CC=CC=2)C=N1.COC1C=C2C(=NC=1)NC=C2.ClC1C=C2C(=NC=1)NC=C2>>[N:54]1([CH2:60][CH2:61][O:62][C:63]2[CH:64]=[C:65]3[C:71]([CH2:25][C:22]4[CH:23]=[CH:24][C:19]([NH:7][CH2:8][C:9]5[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=5)=[N:20][CH:21]=4)=[CH:70][NH:69][C:66]3=[N:67][CH:68]=2)[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1
Reactant: c1cc2cc(OCCN3CCOCC3)cnc2[nH]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C=O)cn1
Agent: COc1cnc2[nH]ccc2c1
Agent: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Br)cc34)cn2)cc1
Agent: Clc1cnc2[nH]ccc2c1
Product: FC(F)(F)c1ccc(CNc2ccc(Cc3c[nH]c4ncc(OCCN5CCOCC5)cc34)cn2)cc1

Procedure:
Additional compounds may be prepared using steps 3 and 4 of Scheme 32, using (5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester 19 or replacing it with (5-Formyl-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester (43, prepared as described in Example 17) and replacing 5-(2-Morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine 79 with an appropriate azaindole, prepared as in Example 29 or 5-methoxy-7-azaindole (prepared as described in Example 31) or with commercially available 5-chloro-7-azaindole. The following compounds were made following this procedure:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[C:5]([CH3:14])=[CH:4][N:3]=1.O[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)[CH3:13])[C:5]([CH3:14])=[CH:4][N:3]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Cc1cnc(Cl)nc1N(C)CCCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cnc(Cl)nc1N(C)CCCOc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.1 %

Procedure:
To a solution of 3-[(2-chloro-5-methyl-4-pyrimidinyl)(methyl)amino]-1-propanol (0.316 g, 1.47 mmol) (prepared in similar fashion as Example 83) and 5-hydroxyindole (0.195 g, 1.47 mmol) in dichloromethane (7 mL) was added triphenylphosphine (1.15 g, 4.40 mmol) and 1,1′-(azodicarbonyl)dipiperidine (1.11 g, 4.40 mmol) under argon. The golden yellow mixture was stirred at rt for 24 h. The desired product (0.117 g, 24%) was obtained after column chromatography (50% hexanes in EtOAc). LC/MS m/z 331.3 (M+H)+, RT 2.76 min.
Reaction SMILES: CS(OCC[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:17]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:20][C:9]1=2)(=O)=O.[C-]#N.[Na+].CS(C)=O.S([O-])(=O)(=O)C>O.C(N(CC)CC)C>[N:21]1([C:19]2[N:18]=[C:17]([N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]=3[N:20]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Agent: CS(=O)(=O)[O-]
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc2c(c1)[nH]c1nc(N3CCCC3)nc(N3CCCC3)c12

Procedure:
A stirred mixture of 9-[2-(methanesulfonyloxy)ethyl]-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (II, EXAMPLE 1 and WO/9626941-A1, 165 g), sodium cyanide (180 g), water (360 mL) and DMSO (3000 mL) are heated at 100° for 18 hr. It is important that the starting mesylate contain traces of triethylamine either left over from its preparation, or added intentionally. The mixture is cooled to 20-25°, diluted with water (approximately 6,000 mL) and filtered. The solid is washed with water to remove excess cyanide, then triturated with acetone. Filtration and drying gives 2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (III), mp 209-211°; NMR (CDCl3) 7.88, 7.22, 7.09, 3.95, 3.67 and 1.98 δ; MS (m/z, FAB, M+H) 308.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH:23]=O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:23]([CH2:22][CH2:21][C:15]3[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([F:12])[CH:14]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(I)cn1CCN
Reactant: COc1ccc(CCC=O)cc1F
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(OC)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (11.500 mmol) and 3-(3-fluoro-4-methoxy-phenyl)-propionaldehyde (2.514 g; 13.800 mmol) afforded 3-ethyl-8-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.70 min.; [M+H]+=429.88 g/mol.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].I[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:6][CH:3]([CH2:4][CH3:5])[C:2]#[C:1][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (40 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 78 mg, 60%).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7](Cl)[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:4]=1.[CH:17]([OH:20])([CH3:19])[CH3:18]>>[C:13]1([CH3:16])[CH:14]=[CH:15][C:10]([C:5]2[N:6]=[C:7]([O:20][CH:17]([CH3:19])[CH3:18])[CH:8]=[C:3]([O:20][CH:17]([CH3:19])[CH3:18])[N:4]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: CC(C)O
Agent: [Na]
Product: Cc1ccc(-c2nc(OC(C)C)cc(OC(C)C)n2)cc1

Procedure:
21.16 g of sodium are dissolved in anhydrous isopropanol and to this solution are added 95.64 g of 4,6-dichloro-2-p-tolylpyrimidine at 60°-65° C. over 15 minutes. The mixture is then heated to the boil and refluxed for a further 4 hours to bring the reaction to completion. Excess isopropanol is then distilled off and the residual oil is taken up in chloroform. The chloroform layer is washed with water, dried over sodium sulfate, and filtered. The solvent is then distilled off, affording 112 g of 2-p-tolyl-4,6-bis-isopropoxypyrimidine in the form of a yellowish oil which is purified by high vacuum distillation. The boiling point is 123° C./5.332 Pascal.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].C(OCC)(=O)C>ClCCl>[CH3:15][C:13]([CH3:12])([O:16][C:17]([N:19]1[CH2:23][CH:22]2[CH:21]([O:9]2)[CH2:20]1)=[O:18])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Reaction time: 4 h
Yield: 39.1 %

Procedure:
80% m-Chloroperbenzoic acid (3.9 g, 0.0226 mole) was added to a solution of 2,5-dihydro-1H-pyrrole-1-carboxylic acid 1,1-dimethylethyl ester (3.55 g, 0.021 mole) in dichloromethane (70 ml) and the mixture was stirred for 24h when more peracid (0.27 g,0.00156 mole) was added and the stirring continued for a further 4h. Ethyl acetate was added and the mixture was washed with 10% sodium carbonate solution. The aqueous phase was extracted with ethyl acetate (50 ml) and the combined organic solution washed with water, dried (MgSO4) and evaporated to leave an oil which was purified by column chromatography on flash silica eluting with 30% ethyl acetate in cyclohexane to give the title compound (1.52 g) as an oil, nmr(δ,CDCl3) includes 1.45(s,9H), 3.42(dd,2H), 3.67(s,2H), 3.78(dd,2H).
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][C:19]=4[CH3:29])[N:14]=3)=[CH:9][C:8]=2[C:30]#[C:31][Si](C)(C)C)[CH2:3]1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:36][C:2]1([F:1])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][C:19]=4[CH3:29])[N:14]=3)=[CH:9][C:8]=2[C:30]#[CH:31])[CH2:3]1
Reactant: Cc1cc(CCC(=O)O)ccc1-c1noc(-c2cnc(N3CCC(F)(F)C3)c(C#C[Si](C)(C)C)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1cc(-c2nc(-c3ccc(CCC(=O)O)cc3C)no2)cnc1N1CCC(F)(F)C1

Procedure:
A solution of 5 mg of 3-(4-(5-(6-(3,3-difluoropyrrolidin-1-yl)-5-(trimethylsilyl)ethynylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoic acid in 200 μL of tetrabutylammonium fluoride (1.0 M in THF) was stirred at rt for 2 h. Purification by HPLC B afforded the title compound: 1HNMR (500 MHz, DMSO) δ 2.48 (m, 4H), 2.86 (t, J=7.3, 2H), 4.09 (t, J=7.3, 2H), 4.24 (t, J=13, 2H), 7.24 (d, J=8.4, 1H), 7.28 (s, 1), 7.92 (d, =8.0, 1H), 8.27 (d, J=2.3, 1H), 8.86 (d, J=2.3, 1H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([O:25][CH3:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:39][C:37]=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([O:25][CH3:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([NH:39][CH3:37])=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CC(=O)O)CS3)cc2c1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)C[C@@H]1CSC(c2cc3cc(OC)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
The compound (83 mg, 0.22 mmol) prepared in Example 48 was dissolved in N,N-dimethylformamide (3 ml). Methylamine (0.17 ml, 2M in THF, 0.33 mmol), EDC (72 mg, 0.38 mmol) and HOBT (60 mg, 0.44 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (39 mg, Yield 46%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH2:8][CH3:9].O.[OH-].[Na+]>C(OCC)C>[CH2:7]([C:10]1[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.1 %

Procedure:
Lithium aluminum hydride (1.16 g) was suspended in diethyl ether (100 mL), a solution (50 mL) of 4-propylbenzoic acid (5.0 g) in diethyl ether was added under ice-cooling, and the mixture was heated under reflux for 2.5 hr. The reaction mixture was ice-cooled, and water (3.0 mL) and aqueous sodium hydroxide solution (1 mol/L, 12 mL) were successively added dropwise. After warming to room temperature, the mixture was stirred for 30 min. The reaction mixture was directly filtered through celite, and the filtrate was evaporated under reduced pressure to give the title compound (4.9 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].CCCCCC.C([Li])CCC.[CH:18]([CH:20]=[CH2:21])=[O:19]>O1CCCC1>[OH:19][CH:18]([C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:20]=[CH2:21]
Reactant: C=CC=O
Reactant: C#CC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(O)C#CC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 741.3 %

Procedure:
Ten grams (0.122 mole) of 3,3-dimethyl-1-butyne was dissolved in 100 ml of anhydrous tetrahydrofuran, and the resulting solution was cooled to -40° C. or less in a dry ice-acetone bath. Under a stream of a nitrogen gas, 81.13 ml (0.122 mole) of a 1.5 M hexane solution of n-butyllithium was added dropwise at -40° C. or less with stirring. After aging the reaction solution at -50° C. for 30 minutes, 6.84 g (0.122 mole) of acrolein was added dropwise at -50° C. or less. After the reaction solution was allowed to stand overnight at room temperature, it was poured into 200 ml of ice water and extracted with two 100-ml portions of ethyl acetate. The organic layers were combined, washed once with 100 ml of a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 125 g of 3-hydroxy-6,6-dimethylhept-1 -ene-4-yne (bp20, 80° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:12][CH:11]=3)=[N:6][CH:7]=2)=[CH:27][CH:26]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Brc1ccc(C#Cc2ccc(OCCN3CCCC3)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)cc3)nc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2.97 g (8.0 mmol) 5-bromo-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine, 2.50 g (16.0 mmol) 4-chloro-phenylboric acid, 462 mg (0.4 mmol) tetrakis-triphenylphosphane-palladium and 8.0 mL of a 2M aqueous Na2CO3 solution in 100 mL 1,4-dioxane is heated for 4 h at 100° C. under an argon atmosphere. The solvent is distilled off i.vac., the residue is stirred with water/EtOAc (1/1, v/v), suction filtered through a fibreglass filter, the organic phase is washed with saturated, aqueous NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (Alox, cyc/EtOAc 2:1). The product fractions are evaporated down, the residue is triturated with diethyl ether, suction filtered and washed with diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.C([O-])([O-])=O.[Na+].[Na+]>C(O)CCC>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCNCCCl
Reactant: Cc1c(N)cccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Cc1c(Cl)cccc1N1CCNCC1
Yield: 78.5 %

Procedure:
To a stirred solution of 3-chloro-2-methylaniline (21.6 g, 0.15 mol) in n-butanol (200 ml) was added bis(2-chloroethyl)amine hydrochloride (30 g, 0.17 mol) at room temperature and allowed to refluxed temperature for 2 days. After cooled to room temperature Na2CO3 (9 g, 0.08 mol) was added and then reaction mixture was refluxed 30 min. The resulting mixture was filtered with n-butanol (100 ml) and collected solid was dried under reduced pressure to be obtained title compound (24.8 g, 81%) as white solid.