Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]=[C:27]=[O:28])=[CH:20][CH:19]=1>>[CH2:25]([NH:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:28])[CH2:24][C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: O=C=NCCc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)NCCc4ccccc4)cc23)CC1
Yield: 64.1 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 12.51 mg (0.0852 mMol) 2-phenethyl isocyanate, 15.8 mg (65%) of the title compound were recovered.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CO>[CH2:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(NCc4ccccc4)nc23)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A mixture of 0.25 gm (1.09 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine, 0.5 gm molecular sieves, and 0.22 mL (2.17 mMol) benzaldehyde in 10 mL methanol was stirred at 40° C. for 5 hours. The reaction mixture was then cooled to room temperature and then 0.124 gm (3.27 mMol) sodium borohydride were added. The reaction mixture was then stirred for 30 minutes at room temperature and then the reaction mixture quenched with 1N sodium hydroxide. The reaction mixture was concentrated under reduced pressure and then the aqueous residue was extracted well with 3:1 chloroform:isopropanol. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 0-10% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:25][CH2:24][C:7]2[N:8]=[C:9](S(C)(=O)=O)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[NH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=1>>[C:1]([N:4]1[CH2:25][CH2:24][C:7]2[N:8]=[C:9]([NH:26][CH2:27][CH2:28][NH:29][C:30]3[N:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: CC(=O)N1CCc2nc(S(C)(=O)=O)nc(-c3ccc(Cl)cc3Cl)c2C1
Product: CC(=O)N1CCc2nc(NCCNc3ccc(C#N)cn3)nc(-c3ccc(Cl)cc3Cl)c2C1

Procedure:
Following Example 7, reaction of 6-acetyl-4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine and 2-(2-aminoethyl-amino)-5-cyanopyridine gave 6-[(2-{[6-acetyl-4-(2,4-dichlorophenyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: CO[CH2:3][N:4]([CH2:12][Si](C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:17]([O:19][C:20](=[O:38])/[C:21](/[CH3:37])=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=1)[CH3:18].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:21]1([CH3:37])[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:3][N:4]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:12]1)=[O:38])[CH3:18]
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a stirred solution of N-methoxymethyl-N-(phenylmethyl)trimethylsilylmethylamine (27 g, 113.7 mmol) and (E)-3-(3-cyclopentyloxy-4-methoxy-phenyl)-2-methyl-acrylic acid ethyl ester (19 g, 62.4 mmol) in CH2Cl2 (50 mL), cooled to 0° C., was added trifluoroacetic acid (1.0 M in CH2Cl2, 22.8 mL, 22.8 mmol). The reaction mixture was stirred at room temperature for 1 hour, then another molar equivalent of N-methoxymethyl-N-(phenylmethyl)trimethylsilylmethylamine (14.8 g, 62.4 mmol) added over 10 minutes. Stirring was continued for 3 hours, then the CH2Cl2 was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1.0 N aqueous HCl (2×50 mL), water, 1.0 N aqueous NaOH solution, water, and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a pale yellow oil. Chromatography on silica gel (9:1, hexanes:ethyl acetate) provided the product as an amber oil (16.7 g, 61% yield). 1H NMR (300 MHz, CDCl3): δ(ppm); 7.39-7.23 (m, 5H, aromatic), 6.91 (s, 1H, aromatic), 6.78 (m, 2H, aromatic), 4.75 (m, 1H), 4.18 (q, 2H, OEt), 3.86 (m, 1H), 3.81 (s, 3H, OCH3), 3.75 (d, 1H, J=13.2 Hz), 3.62 (d, 1H, J=13.2 Hz), 3.20 (d, 1H, J=9.5 Hz), 3.01 (m, 1H), 2.91 (m, 1H), 2.51 (d, 1H, J=9.5 Hz), 1.93-1.58 (M, 8H, cyclopentyl), 1.28 (t, 3H, OEt), 0.9 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][N:32]1[CH2:31][CH2:30][CH:29]([O:28][C:27]2[CH:35]=[CH:36][C:24]([F:23])=[CH:25][CH:26]=2)[CH2:34][CH2:33]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CI)CC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Triphenylphosphine bound to cross-linked polystyrene resin (2.16 g, mol/g, 6.47 mmol) is suspended in dry DCM (50 ml) at ambient temperature under a nitrogen atmosphere. Iodine (1.64 g, 6.47 mmol) is added and the reaction mixture stirred for 15 minutes. Imidazole (0.50 g, 7.35 mmol) is then added and the reaction mixture is stirred for a further 15 minutes. A solution of (R)-3-.tert.-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (prepared as described by D. Gani et al J. Chem. Soc. Perkin Trans. 1, 2513–2525, 1997 (0.909 g, 2.94 mmol) in dry DCM (10 ml) is added and the reaction mixture is stirred at reflux for 1 hour. The polymer is removed by filtration, and the filtrate is first washed with aqueous 5% sodium thiosulphate solution and then water. The organic phase is dried over MgSO4 and evaporated to yield (R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester as a crude oil. A solution of (R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester (1.017 g, 2.43 mmol) and 4-(4-fluoro-phenoxy)-piperidine (0.569 g, 2.916 mmol) in DMF (25 ml) is treated with triethylamine (0.406 ml, 2.916 mmol). The reaction mixture is stirred at ambient temperature for 60 hours, and then partitioned between ethylacetate and water. The ethylacetate phase is dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 2:1 hexane/ethylacetate) to afford (R)-3-tert-butoxycarbonylamino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. [MH]+ 487.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:18][CH:17]=1
Reactant: COc1ccccc1NC(=O)COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1NCCOc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 59.8 %

Procedure:
N1-(2-Methoxyphenyl)-2-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenoxy}acetamide (100 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A borane-tetrahydrofuran complex (1.0 M solution: 1.08 ml) was then added to the solution, and the mixture was heated under reflux for 5 hr. 1 N Hydrochloric acid was added thereto, and the mixture was further heated under reflux for 30 min. A 5% aqueous sodium hydroxide solution was added to the reaction solution, the mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (58 mg, yield 60%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][C:20]=1[O:27][CH3:28].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[OH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=2)[C:37]([O:39][CH3:40])=[O:38])=[C:20]([O:27][CH3:28])[CH:21]=1
Reactant: COc1cc(CO)ccc1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COC(=O)C(Oc1ccc(CO)cc1OC)c1ccccc1
Yield: 25.2 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.49 mmol) of 4-hydroxy-3-methoxybenzyl alcohol was alkylated with 1.64 g (7.14 mmol) of methyl 2-bromophenylacetate to afford 0.495 g (25%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([OH:11])[CH2:3]1.[H-].[Na+].F[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C@@H:24]3[CH2:28][CH2:27][CH2:26][N:25]3[CH3:29])=[N:22][N:23]=2)[CH:20]=1>CN(C=O)C.O>[CH3:29][N:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[C:21]1[N:19]2[CH:20]=[C:15]([O:11][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]([NH2:1])[CH2:3]3)[CH:16]=[CH:17][C:18]2=[N:23][N:22]=1
Reactant: CN1CCC[C@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1C[C@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
(1S,3S)-3-Amino-indan-1-ol (110 mg, 0.74 mmol) was added to a suspension of NaH (60% in mineral oil, 87 mg, 2.17 mmol) in anhydrous DMF (5 mL) at RT and stirred for 20 min. Intermediate 5b (160 mg, 0.72 mmol) was then added in one portion and the mixture heated at 60° C. for 3 h. After cooling the mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as give a foam (132 mg, 52%). LCMS (Method 1): Rt 0.34 min, m/z 350 [MH+]. 1H NMR (300 MHz, CDCl3): 1.95-2.16 (6H, m), 2.24 (3H, s), 2.26-2.45 (2H, m), 2.77 (1H, ddd, J 14.1, 7.0, 2.0), 3.23-3.30 (1H, m), 4.02-4.09 (1H, m), 4.71 (1H, t, J 6.8), 5.68 (1H, dd, J 6.2, 1.9), 7.04 (1H, dd, J 9.9, 2.2), 7.29-7.50 (4H, m), 7.64 (1H, dd, J 9.9, 0.9), 8.35 (1H, d, J 2.2).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]([CH:57]2[CH2:65][C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:58]2)[CH2:43][C:44]([NH:46][CH:47]([CH:54]([CH3:56])[CH3:55])[C:48](=[O:53])[C:49]([F:52])([F:51])[F:50])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:29][CH:28]=1)(O)=[O:25]>>[CH2:12]([O:19][C:20]([CH2:21][NH:22][C:24]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]([CH:57]2[CH2:58][C:59]3[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH2:65]2)[CH2:43][C:44]([NH:46][CH:47]([CH:54]([CH3:56])[CH3:55])[C:48](=[O:53])[C:49]([F:51])([F:52])[F:50])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:31][CH:32]=1)=[O:25])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)C(NC(=O)CN(C(=O)[C@@H](NC(=O)c1ccc(C(=O)O)cc1)C(C)C)C1Cc2ccccc2C1)C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C(NC(=O)CN(C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCC(=O)OCc2ccccc2)cc1)C(C)C)C1Cc2ccccc2C1)C(=O)C(F)(F)F
Yield: 97.1 %

Procedure:
3(RS)-[[4-[(Benzyloxycarbonyl)methylaminocarbonyl]phenylcarbonyl]-L-valyl-N-(2-indanyl)glycyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (250 mg) was prepared from glycine benzyl ester p-toluenesulfonate (118 mg) and 3(RS)-[(4-carboxyphenylcarbonyl)-L-valyl-N-(2-indanyl)glycyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (206 mg) by a similar method to that of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].O[C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: Cc1ccc(O)c(Cl)c1
Reactant: COC(=O)[C@@H](C)O
Product: COC(=O)[C@H](C)Oc1ccc(C)cc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the 2-chloro-4-methylphenol instead of the m-cresol and the (R)-methyl 2-hydroxypropanoate instead of the (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22][C:23]([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)=O)[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N>CO.C(Cl)Cl>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:14]([C@H:23]([C:25]4[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=4)[CH2:22][N:18]4[CH2:19][CH2:20][CH2:21][C@H:17]43)=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)c1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 54 %

Procedure:
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl-pyrrolidin-1-yl}-1-m-tolyl-ethanone. Prepared as described in Example 8, Step 1, on a 2.70 mmol scale, to give 610 mg (54%) of the desired product as an orange oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C27H36N2O2, 420.3; m/z found, 421.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:12])[CH2:5][CH:6]2[Cl:11].C(N(CC)CC)C.[Cl:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>O1CCCC1>[Cl:20][C:21]1[C:22]([C:23]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]([CH3:12])[CH2:5][CH:6]3[Cl:11])=[O:24])=[CH:26][CH:27]=[CH:28][N:29]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CC1CC(Cl)c2cccc(N)c21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CC(Cl)c2cccc(NC(=O)c3cccnc3Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 1 g (5.5 mmol) of 4-amino-1-chloro-3-methylindane and 0.7 g (6.9 mmol) of triethylamine in 15 ml of tetrahydrofuran was added 1.1 g (6.2 mmol) of 2-chloronicotinic acid chloride under ice cooling, and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried over Glauber's salt and then concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=2/1) to obtain 1.3 g of white crystals (Compound No. 6 shown in Table 2) in a yield of 75%.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH3:22][N:23]1CCCC1=O>>[C:22]([C:2]1[C:10]2[C:9]([NH:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1)#[N:23]
Reactant: COc1ccc(C(C)Nc2ncnc3scc(Br)c23)cc1
Reactant: CN1CCCC1=O
Product: COc1ccc(C(C)Nc2ncnc3scc(C#N)c23)cc1
Temperature: 130 °C
Yield: 30 %

Procedure:
5-Bromo-N-[1-(4-methoxyphenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (250 mg, 0.69 mmol) and cuprous cyanide (310 mg, 3.4 mmol, 5 eq.) were combined in dry N-methylpyrrolidinone (NMP) (4 mL) and heated to 130° C. for 19 hours. After cooling, the volatiles were removed by Kugelrohr distillation at 0.1 mm and the residue was taken up in EtOAc/2 molar NH4OH. The organic phase was washed with water, brine, dried (Na2SO4) and evaporated. The residue was chromatographed on a 50 mm×250 mm YMC-AQ RP HPLC column eluting with 70 percent acetonitrile (ACN) to give 61 mg (30 percent) of the purified off-white solid.
Reaction SMILES: C[C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([CH2:26]C(Cl)=O)=[CH:24][CH:23]=1.Cl>ClCCl>[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:2][CH3:10])=[O:8])=[CH:30][CH:31]=1
Reactant: O=C(Cl)Cc1ccc(OCc2c(F)cccc2F)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Cc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Meldrum's acid (0.846 g, 5.8 mmol) in dichloromethane (5 ml) was added pyridine (2 ml) over a period of 10 minutes at 0° C. To this solution was added 4-(2,6-Difluorobenzyloxy)benzylcarbonyl chloride (Step D, 1.71 g, 5.7 mmol) in dichloromethane (5 ml), which resulted in an orange solution. The dark orange solution was stirred for 1 hour at 0° C., allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was diluted with dichloromethane and poured onto 2M HCl and ice. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed twice with 2M HCl and brine, dried over Na2SO4, filtered and concentrated to a solid. The solid was suspended in abs EtOH (15 ml) and refluxed for 2.5 hours. The solvent was removed in vacuo to give a dark oil. The residue was purified by flash chromatography on silica gel column (hex:ethyl acetate, 2:1) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].C([O-])([O-])=O.[K+].[K+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][O:6][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: COC(=O)C(C)(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a mixture of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (13.2 g, 0.1 mol), K2CO3 (20 g, 0.14 mol) and DMAP (6.2 g, 0.05 mol) in DCM (100 mL) was added p-toluenesulfonyl chloride (19 g, 0.1 mol). The mixture was stirred at room temperature overnight, then filtered. The filtrate was washed with HCl aq. (1 M) and water, dried over anhydrous Na2SO4 and concentrated to give the title compound (15 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH:15]=[CH2:16])[CH3:14])(=[O:11])[CH3:10].[C:23](Cl)(=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C1COCC1>[C:23]([CH2:10][C:9]([O:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH:15]=[CH2:16])[CH3:14])=[O:11])(=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCC(=O)Cl
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)CCCCCCCC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide in the amount of 133.7 mL (2.0 M, 0.267 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled -78° C. Linalyl acetate in the amount of 24.73 g (0.126 mol) is dissolved in THF (40 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of nonanoyl chloride in the amount of 21.88 g (0.119 mol) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (60 mL). The mixture is poured into a separatory funnel containing ether (160 mL) and water (275 mL). The aqueous layer is extracted with ether (160 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate dissolved in hexane) to give an oil. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][C@@H:37]2[CH3:42])[CH3:35])=[CH:4][N:3]=1.CCN(CC)CC.[CH3:50][S:51](Cl)(=[O:53])=[O:52].[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:51]([CH3:50])(=[O:53])=[O:52])[CH2:38][C@@H:37]2[CH3:42])[CH3:35])=[CH:4][N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNC[C@@H]4C)cnc3F)nc(C)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)nc(C)n2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A solution of 6-(2-fluoro-5-((1R)-1-((2S)-2-methyl-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.200 g, 0.350 mmol) in CH2Cl2 (3 mL) at −20° C. was treated with NEt3 (0.488 mL, 3.50 mmol) followed by methanesulfonyl chloride (0.083 mL, 1.051 mmol). The mixture stirred at −20° C. for 30 minutes. 1 M NaOH (aq.) and CH2Cl2 were then added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 60% to 100% EtOAc in hexane, to provide 6-(2-fluoro-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.130 g, 0.200 mmol, 57.2% yield) as a white foam. m/z (ESI, +ve) 649.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.42 (dd, J=9.29, 2.45 Hz, 1H); 8.14 (d, J=1.17 Hz, 1H); 7.18 (d, J=7.82 Hz, 4H); 6.81-6.89 (m, 5H); 4.74 (br. s., 4H); 4.04 (q, J=6.78 Hz, 1H); 3.79 (s, 6H); 3.28-3.37 (m, 1H); 3.16-3.24 (m, 1H); 3.12 (dd, J=10.95, 2.93 Hz, 1H); 2.85-3.01 (m, 2H); 2.77 (s, 3H); 2.63-2.70 (m, 2H); 2.62 (s, 3H); 1.44 (d, J=6.85 Hz, 3H); 1.10 (d, J=6.26 Hz, 3H).