Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[Li]CCCC.[C@@H:21]12[C:30](=[O:31])[O:29][C:27](=[O:28])[C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26]2.[Cl-].[NH4+]>C1COCC1.O>[CH:11]1([O:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[C:30]([C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[C:27]([OH:29])=[O:28])=[O:31])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)[C@H]2CCCC[C@H]2C(=O)O)cc1OC1CCCC1
Temperature: -90 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
4-Bromo-2-cyclopentyloxy-1-methoxybenzene (16.3 g, 60 mmol) was dissolved in THF (200 ml) and cooled with an ethanol/N2 bath to -90° C. BuLi (41 ml, 66 mmol) was added dropwise while keeping the temperature below -80° C. and stirred for another 15 min after the last addition. This mixture was then quickly added under a nitrogen atmosphere to a cooled solution (-90° C.) of cis-1,2-cyclohexanedicarboxylic anhydride (11.1 g, 72 mmol) in THF (200 ml). After stirring for 2 h at -80° C. solid ammoniumchloride was added and the reaction mixture was allowed to warm slowly to room temperature. Water (300 ml) was added and the anorganic layer was washed with ethyl acetate (200 ml). The combined organic extracts were washed with water (300 ml) and brine (2×300 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane and purified by chromatography (petroleum ether (60°-95° C.)/ethyl acetate: 7/13) and crystallized from petroleum ether (60°-95° C.)/ethyl acetate to give the title compound (10.1 g) as a white solid. M.p. 120°-121° C.
Reaction SMILES: [C:1]([Cu])#N.C[Li].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]2[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:16]([CH2:23][CH3:24])=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:10]=[C:9]([Cl:33])[N:8]=1>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]2[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:16]([CH2:23][CH3:24])=[C:15]([CH3:1])[N:14]=2)[CH:10]=[C:9]([Cl:33])[N:8]=1
Reactant: N#C[Cu]
Reactant: C#CCn1c(-c2cc(Cl)nc(Cl)c2)nc(OS(=O)(=O)C(F)(F)F)c(CC)c1=O
Agent: [Li]C
Solvent: C1CCOC1
Product: C#CCn1c(-c2cc(Cl)nc(Cl)c2)nc(C)c(CC)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a stirred, cold (-78° C.) solution of CuCN (1.91 g, 20 mmol) in 100 mL of THF was added methyllithium (30 mL, 42 mmol, 2.1 equiv, 1.4M in diethyl ether) over 10 min. After stirring for 15 min, this solution was added over 10 min via a canula to a cold (-78° C.) solution of 2-(2,6-dichloro-4-pyridyl)-5-ethyl-3-propargyl-6-trifluoromethanesulfonyloxy-4(3H)-pyrimidinone in 20 mL of THF. The reaction mixture was stirred for 30 min, quenched with 15 mL of 10% concentrated NH4OH/saturated NH4Cl, diluted with 200 mL of ethyl acetate and warmed to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give a semi oil. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane, 2/8) to afford 2.29 g (71%) of 2-(2,6-dichloro-4-pyridyl)-5-ethyl-6-methyl-3-propargyl-4(3H)-pyrimidinone as a white solid: mp 143-144° C.; IR (KBr) 3220, 2125, 1668, 1584, 1541, 1515, 1367 cm-1 ; 1H NMR (270 MHz, CDCl3) δ1.16 (t, J=7.6 Hz, 3H), 2.35 (s, 3H), 2.43 (t, J=2.6 Hz, 1H), 2.62 (q, J=14.8 Hz, 2H), 4.56 (d, J=2.6 Hz, 2H), 7.60 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:15][N:16]([CH2:18][C:19](Cl)=[O:20])[CH3:17]>>[CH3:15][N:16]([CH3:17])[CH2:18][C:19]([N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:20]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Product: CN(C)CC(=O)N1CCCc2ccc([N+](=O)[O-])cc21

Procedure:
Using the procedure outlined in Description 4 followed by silica SPE chromatography eluting with 20% EtOAc/MeOH the title compound was prepared from 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (178 mg, 1 mmol) and dimethylaminoacetyl chloride hydrochloride (174 mg, 1.1 mmol) as a yellow solid (103 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.74 (d, 1H), 7.92 (dd, 1H), 7.28 (d, 1H), 3.87 (m, 2H), 3.25 (s, 2H), 2.87 (t, 2H), 2.35 (s, 6H), 1.95 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:26])[C:16]=2[N:15]=[C:14]1[CH2:27][CH3:28].[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[NH2:26][C:17]1[C:16]2[N:15]=[C:14]([CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Reaction time: 0.08 h
Yield: 78.8 %

Procedure:
Triethylamine (0.59 mL, 4.3 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) in chloroform (100 mL). The solution was stirred in an ice bath for 5 min. Phenyl isocyanate (0.38 mL, 3.5 mmol) was slowly added. The resulting precipitate was isolated by filtration, washed with chloroform (4×30 mL), and then dried in an Abderhalden drying apparatus overnight to provide 1.11 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as a white solid, m.p. 179.7-181.4° C. Analysis: Calculated for C23H26N6O.0.6H2O: % C, 66.84; % H, 6.63; % N, 20.33. Found: % C, 67.20; % H, 6.61; % N, 20.46.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:27][C:16]1[CH:17]=[CH:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:20][C:15]=1[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=1)[C:8]([NH:7][CH2:6][C:5]1[CH:29]=[CH:30][CH:31]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=1)=[O:28])=[O:39]
Reactant: O=C(O)c1cccc(O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(O)c2)c1
Reaction time: 18 h
Yield: 29.6 %

Procedure:
To a mixture of 4.1c (91 mg, 0.20 mmol), 3-hydroxybenzoic acid (28 mg, 0.20 mmol), and diisopropylethylamine (104 □L, 0.60 mmol) in DMF (2 mL) was added HATU (76 mg, 0.20 mmol) and the solution stirred for 18 h. The solvent was removed and the resulting residue purified by reverse-phase HPLC eluting with a water/acetonitrile gradient containing 0.1% TFA and lyophilized to give 34 mg (30%) of the product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:17]=2)[CH:8]=[C:9]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:33].[Na+]>CCO.O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:12])[C:14]([NH2:15])=[O:33])[CH:8]=[C:7]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[C:19]([CH3:28])=[C:18]([S:29](=[O:31])(=[O:30])[NH2:32])[CH:17]=2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C#N)c2)n1CC1CCCCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C(N)=O)c2)n1CC1CCCCC1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of compound 45 (455 mg, 1.0 mmol) and NaOH (3.2 g, 80 mmol) in EtOH (10 mL) and water (10 mL) was stirred at reflux overnight, cooled to rt, concentrated and redissolved in H2O (30 mL), acidified with 1N HCl solution to pH=6. The formed solid was collected by filtration, washed with water and dried under vacuum. The residue was purified by CC (DCM/MeOH=50/1) to give compound 47 (400 mg, 85%) of as a white solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[S:16][C:14]=2[N:15]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:9])=[O:8])=[CH:3][CH:2]=1.[OH:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C(N(CC)CC)C>C1COCC1>[O:26]=[C:21]1[CH2:22][CH2:23][C:24](=[O:25])[N:20]1[O:19][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:1]2[CH:6]=[CH:5][C:4]([C:7]([Cl:9])=[O:8])=[CH:3][CH:2]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(Cl)c1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(-c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A solution of 1.67 g (6.0 mmol) of 11 in 65 mL of dry THF was treated with 710 mg (6.17 mmol) of N-hydroxysuccinimide, followed by 0.835 mL (6.0 mmol) of triethylamine. The reaction was stirred at room temperature for 2 hours after which time it was filtered to remove triethylamine HCl. The filtrate was concentrated at reduced pressure to yield 2.0 g (93%) of 12 as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[N:7]1[CH:14]=[CH:13][C:11](=O)[NH:10][C:8]1=[O:9].C[Si](C)(C)[NH:17][Si](C)(C)C.C(N)=O>CO>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[N:7]1[CH:14]=[CH:13][C:11]([NH2:17])=[N:10][C:8]1=[O:9]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=c1ccn(C2CC2CCO)c(=O)[nH]1
Solvent: NC=O
Solvent: CO
Product: Nc1ccn(C2CC2CCO)c(=O)n1
Temperature: 140 °C
Reaction time: 85 h

Procedure:
To 79 mg (0.42 mmol) of 1-(2'-(2"-hydroxyethyl)cyclopropyl) uracil, the product of Step B of Example 8, is added 0.44 mL (2.1 mmol) of hexamethyldisilazane and 0.034 mL (0.82 mmol) of formamide and the resultant mixture is heated with stirring in a sealed tube at 140° C. After 85 h, 10 mL of methanol is added to the cooled reaction mixture, the tube resealed and heated to 65° C. After 3 h at 65° C., the cooled reaction mixture is concentrated under reduced pressure. The residue is dissolved in 10 mL of water and the resultant aqueous solution treated with 50 mg of Darco G-60 charcoal, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with a gradient of methanol in methylene chloride from 100% methylene chloride to 30% methanol affords the title compound.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1C)#[CH:2].BrC1C2C(=CC=CC=2)C=CC=1C.Br[C:27]1C2C(=CC=CC=2)C=C[C:28]=1[S:37]CC>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:37][CH2:28][CH3:27])#[CH:2]
Reactant: C#Cc1c(C)ccc2ccccc12
Reactant: CCSc1ccc2ccccc2c1Br
Agent: Cc1ccc2ccccc2c1Br
Product: C#Cc1c(SCC)ccc2ccccc12

Procedure:
1-Ethynyl-2-ethylthionaphthalene was prepared in a similar manner to 1-ethynyl-2-methylnaphthalene, except that 1-bromo-2-methylnaphthalene was replaced by 1-bromo-2-ethylthionaphthalene.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:68]=[CH:67][C:39]([O:40][CH2:41][C@H:42]([NH:47][C:48]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.O>[NH2:27][C:4]1[N:3]=[C:2]([C:36]2[CH:68]=[CH:67][C:39]([O:40][CH2:41][C@H:42]([NH:47][C:48]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=1
Reactant: COC(=O)[C@H](COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)[C@H](COc1ccc(-c2cc(OC(c3ccc(-c4cccc(F)c4)cc3)C(F)(F)F)nc(N)n2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4-chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine (80 mg, 0.20 mmol), (S)-methyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(tritylamino)propanoate (113 mg, 0.20 mmol), dichlorobis(triphenylphosphine)palladium (2 mg, 0.03 mmol), and Na2CO3 (42 mg, 0.40 mmol) were added to a mixture of ethanol (5 mL) and water (5 mL) in a round-bottom flask. The flask was heated to reflux for 8 hours. The reaction mixture was cooled and solvent was removed. The residue was purified by chromatography to get (2S)-methyl 3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenoxy)-2-(tritylamino)propanoate, which was deprotected by TFA and LiOH respectively to afford 50 mg of (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenoxy)propanoic acid as the HCl salt. 1H NMR (300 MHz, CD3OD): δ 7.95 (m, 2H), 7.71 (s, 3H), 7.61 (m, 2H), 7.48 (m, 2H), 7.26 (m, 1H), 7.11 (m, 1H), 7.01 (s, 1H), 6.78 (m, 1H), 4.65 (m, 1H), 4.40-4.55 (m, 3H); M+1=543.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)[C:7](=[NH:17])[C:6]=2[CH:18]=1.O=[C:20]([CH3:24])[C:21](=[S:23])[NH2:22]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:9][CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13]3)[C:7]3([NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:17]3)[C:6]=2[CH:18]=1
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=N
Reactant: CC(=O)C(N)=S
Solvent: CO
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(=S)N1
Temperature: 60 °C
Reaction time: 24 h
Yield: 21.4 %

Procedure:
5-Bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-imine (Example 29 Step 2, 1.37 g, 4.41 mmol) and 2-oxopropanethioamide (Intermediate 2, 0.909 g, 8.81 mmol) were dissolved in dry MeOH (25 mL) and the resulting orange solution was heated at 60° C. under a nitrogen atmosphere overnight. More 2-oxopropanethioamide (400 mg) was added and stirring continued. After 24 h the mixture was allowed to cool to r.t. and the solvent was evaporated. Purification by flash chromatography using a gradient of 0-100% EtOAc in heptane afforded 373 mg of the title compound (21% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (m, 1 H), 1.47 (m, 3 H), 1.87 (m, 2 H), 1.97 (m, 2 H), 2.29 (s, 3 H), 3.13 (s, 3 H), 4.11 (m, 1 H), 6.99 (d, 1 H), 7.16 (d, 1 H), 7.48 (dd, 1 H); MS (ES+) m/z 396 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[CH:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:1][C:3]3[CH:18]=[CH:17][C:6]([O:7][C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=4)=[CH:5][CH:4]=3)[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(C4CCCCC4)CC3)cc2)nc1
Yield: 32.6 %

Procedure:
Using a method similar to Example 334, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.299 g, 1.23 mmol), 1-cyclohexyl-piperazine (0.208 g, 1.24 mmol), and sodium borohydride (0.107 g, 2.83 mmol) in methanol (12 mL) provides 0.158 g (32%) of the title compound as a white solid (chromatography solvent: 20:1→10:1 methylene chloride:methanol). High resolution mass spectrum (electrospray): m/z calc for C23H31N4O2 395.2447, found 395.2461; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=2.4, 8.8 Hz), 7.48-7.43 (m, 2H), 7.18-7.13 (m, 2H), 7.04 (d, 1H, J=8.3 Hz), 3.61 (s, 2H), 2.82-2.53 (m, 8H), 2.39-2.29 (m, 1H), 2.03-1.96 (m, 2H), 1.91-1.83 (m, 2H), 1.73-1.66 (m, 1H), 1.40-1.15 (m, 5H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[N:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CS(C)=O>C(O)C>[N:17]1([CH:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Solvent: CCO
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCC(N4CCCCC4)CC3)cc2)[nH]c1=O

Procedure:
A mixture of 10.7 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile [J. Med. Chem. 14, 342 (1971)] and 16.8 g. of 4-piperidinopiperidine in 140 ml. of dimethyl sulfoxide is stirred and heated at 95°-100° for 50 hours. The mixture is cooled and diluted with 450 ml. of 95% ethanol. The resulting precipitate of 6-[p-(4-piperidinopiperidino)phenyl]-1,2-dihydro-2-oxonicotinonitrile is collected by filtration, washed with 95% ethanol and dried; m.p. 288°-293° (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[K+].N[C@H](C(O)=O)CCSC.CCOC(C)=O>COCCOC>[Cl:1][C:2]1[N:3]=[C:4]([Cl:18])[C:5]2[CH2:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)([CH3:19])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Agent: CSCC[C@H](N)C(=O)O
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(F)cc2)CCc2c(Cl)nc(Cl)nc21
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, (Preparation S, 3.56 g, 12.57 mmol) in DME (Volume: 84 mL) at −78° C. was added KHMDS (0.91 M in THF, 15.20 ml, 13.83 mmol) dropwise. After 10 min, Met (2.36 mL, 37.7 mmol) was added. The reaction was kept at −78° C. for 10 min, then allowed to come to rt. An aliquot taken while the reaction was still cool was quenched with water and extracted with EtOAc. TLC (10% EtOAc/Hex) and LC/MS showed the clean conversion to a new product. The bulk of the material was then quenched and extracted as above. The combined organic extracts were dried over MgSO4, filtered, and the solvent removed in vacuo. SG chromatography (0 to 40% EtOAc/Hex) gave 2,4-dichloro-7-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.01 g, 10.13 mmol, 81% yield). LC-MS (*M*+H)+=293.1 (*product reacts with methanol during analysis*). 1H NMR (500 MHz, CDCl3) δ ppm 7.21-7.29 (2H, m), 6.96-7.04 (2H, m), 2.88-3.02 (2H, m), 2.62 (1H, ddd, J=13.28, 7.93, 5.04 Hz), 2.26-2.35 (1H, m), 1.68 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1.C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH2:18][C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c2ccc(Br)cc2c1Cc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of 5-bromo-2-methyl-1H-indole (J. Chem. Soc., 1428 (1965)) (2.0 g) and 3-pyridinecarboxaldehyde (1.02 g) in dry dichloromethane (20 ml) was added dropwise over 10 minutes to a stirred solution of triethylsilane(3.30 g) in trifluoroacetic acid (20 ml) at 0° C. The solution was stirred at 0° C. for 30 minutes and then evaporated under vacuum, keeping the temperature below 35° C. The residue was dissolved in dichloromethane, and the solution was washed with 2N sodium hydroxide, water and dried (MgSO4). The solution was evaporated and the residue was chromatographed on silica gel, using dichloromethane/methanol (50:1) as eluent. The product fractions were combined and evaporated, and the residue was crystallised from ether to give the title compound (2.15 g), m.p. 188°-190° C. Found: C,59.62; H,4.43; N,9.26. C15 H13BrN2 requires: C,59.82; H,4.35; N,9.30%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH2:15]([OH:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:17][CH2:15][CH3:16])=[O:12]
Reactant: CCO
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1[C@@H](/C=C/C(=O)OC)C1(C)C

Procedure:
Using the procedure of Example 3, 2.7 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in 12.5 ml of benzene and 1 ml of ethanol were reacted to obtain 1.31 g of ethyl (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+93°±1.5° (c=1% in chloroform).
Reaction SMILES: [CH2:1]([NH:5][NH2:6])[CH2:2][CH:3]=[CH2:4].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]([NH:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[O:16])=[CH:10][N:9]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([N:5]([C:12]1[C:11]([C:15]([NH:17][C:18]2[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:24])=[O:16])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=1)[NH2:6])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCNN
Reactant: O=C(Nc1c(Cl)cccc1Cl)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCN(N)c1nc(Cl)ncc1C(=O)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A solution of 230 mg (2.7 mmol) of 3-butenylhydrazine in 10.5 mL of THF was cooled to 0° C. and treated sequentially with 800 mg (2.4 mmol) of 2,4-dichloro-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide and 370 μl (2.6 mmol) of triethylamine. The resulting yellow slurry was warmed to room temperature and stirred for 25 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 99.5:0.5) to give the title compound 85. 1H-NMR (DMSO-d6) δ 3.17 (d, J=5.2 Hz, 2H), 3.31 (s, 2H), 3.80 (t, J=7.3 Hz, 2H), 5.04 (d, J=10.3 Hz, 1H), 5.13 (d, J=17.1 Hz, 1H), 5.77-5.88 (m, 1H), 7.35 (t, J=8.3 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 8.15 (s, 1H), 10.19 (s, 1H). Mass Spectrum (ESI) m/e=385.9 (M+1).