Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[CH:40][CH:41]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[N:38][C:39]([NH:42][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][CH3:21])[C:7](=[O:22])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:40][CH:41]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: COCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 29.8 %

Procedure:
8-Cyclopentyl-2-methanesulfiny-6-methoxymethyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.5 g, 7.78 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.99 g, 10.73 mmol) were heated to reflux in toluene (25 mL) for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4-[6-(8-cyclopentyl-6-methoxymethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (1.24 g, 30.5%). 1H NMR δ (400 MHz, CDCl3) 8.59 (s, 1H), 8.26 (d, J=9.3 Hz, 1H), 7.97 (d, J=2.7 Hz, 1H), 7.6 (t, J=1.5 Hz, 1H), 7.38 (dd, J=2.7, 9.0 Hz, 1H), 5.89 (m, 1H), 4.55 (d, J=1.2 Hz, 1H), 3.66 (q, J=7.1 Hz, 2H), 3.60 (m, 4H), 3.11 (m, 4H), 2.34 (m, 2H), 2.07 (m, 2H), 1.88 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.30 (t, J=6.8 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[S:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[O:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Reactant: Cc1ccc(-c2nc(CCl)co2)s1
Product: Cc1ccc(-c2nc(COc3cccc(CCCn4ccnc4)c3)co2)s1
Yield: 71 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to give 4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole. The yield was 71%. Oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11]O.S(Cl)([Cl:15])=O>ClCCl>[Cl:15][CH2:11][C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(CO)oc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(CCl)oc2ccccc12
Reaction time: 2 h

Procedure:
To a solution of (3-methyl-benzofuran-2-yl)-methanol (1.12 g, 6.9 mmol) in 12 mL of dichloromethane was added 2.8 mL of thionyl chloride. The color of the reaction turned from pink initially to light yellow. After 2 h the reaction was worked up and 2-chloromethyl-3-methyl-benzofuran was obtained in quantitative yield. 1H NMR (400 MHz, CDCl3) δ ppm 2.3 (s, 3 H) 4.7 (s, 2 H) 7.2 (m, 1 H) 7.3 (m, 1 H) 7.5 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2C=CC=C[CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])[CH:5]=[CH:6][CH:7]=1.C(O)(C)C>CCCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:19][CH3:20])[CH2:9][C:10]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O/N=C(\CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: CCC(CC(=NO)c1ccncc1)c1cccc(Br)c1

Procedure:
As a byproduct from the crude reaction mixture of example 12, step 2, HPLC separation (Chiralpak AD column, 10% isopropanol in n-heptane) provided 3-(3-bromo-phenyl)-1-pyridin-4-yl-pentan-1-one oxime as a mixture of E and Z isomers (4:1) as a colorless oil, MS (ESI+): m/z=333.0 ([M+H]+, 1Br).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCN(CCCCC2CCCCN2)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Product: O=C1Nc2cccnc2N(C(=O)N2CCCCC2CCCCN2CCCCC2)c2ccccc21
Yield: 41 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-(1-piperidinyl)butyl]piperidine in a yield of 41% of theory. Colourless crystals, m.p. 199°-201° C. (after being recrystallised twice from ethanol using animal charcoal).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][CH2:10]2)[CH2:7][CH2:6]3.[ClH:25]>C(Cl)(Cl)Cl>[Cl:25][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Cl)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2α,3α-Epoxy-5α-pregn-16-ene-11,20 -dione (250 mg.) in chloroform (10 ml.) was shaken with concentrated hydrochloric acid (8 ml.) for 30 minutes. More chloroform was added, and the organic solution was washed with water, sodium bicarbonate solution and water. It was then dried over magnesium sulphate and evaporated to give a colourless oil which was recrystallised from methanol to give title compound (160 mg.) as colourless prisms, m.p. 209°-212° (decomp.), [α]D + 83° , λmax. 234 nm (ε 8,350) (EtOH).
Reaction SMILES: Cl.[C:2]1([C@@H:8]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]([CH3:32])=O>>[CH:30]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][O:10][CH2:9][C@H:8]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:14]1)([CH3:32])[CH3:29]
Reactant: CC(C)=O
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)OCc1ccccc1
Agent: Cl
Product: CC(C)N1CCC(COC[C@H](NC(=O)OCc2ccccc2)c2ccccc2)CC1

Procedure:
Using alkylation method A, benzyl N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]carbamate hydrochloride (3.7 g, 0.91 mmol) and acetone (2.3 g, 40 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 1.1 g (29%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=427.2 [M+H]+.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[CH2:22]([N:24](CC)CC)C>C(Cl)Cl>[CH3:22][NH:24][C@@H:9]1[C:14]2[C:15](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:16][CH2:7][C@H:8]1[N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O[C@@H]1CCc2ccccc2[C@H]1N1CCCC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 56.8 %

Procedure:
A solution of methanesulfonyl chloride (10.3 g) in methylene chloride (50 ml) was added rapidly in drops to a stirred and cooled (0.5° C.) solution of trans-1,2,3,4-tetrahydro-2-hydroxy-1-(pyrrolidin-1-yl)naphthalene (10.3 g) and triethylamine (10 g) in methylene chloride (100 ml). After the addition was complete, the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was treated carefully with a 33% solution of methylamine in ethanol (125 ml) and the mixture was stirred at reflux for 2 hours followed by evaporation of the solvent under reduced pressure. The residue was treated with water and extracted twice with ether. The combined ether extracts were washed with 2N sodium hydroxide and then with water, dried over magnesium sulfate and evaporated under reduced pressure. The residual viscous liquid was distilled under vacuum to yield trans-1,2,3,4-tetrahydro-1-methylamino-2-(pyrrolidin-1-yl)naphthalene (6.2 g), b.p. 126°-134°/0.25 torr.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>N1C=CC=CC=1.CCOC(C)=O>[S:11]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: CCOC(=O)C1CC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-hydroxycyclobutanecarboxylate (10.2 g, 78.4 mmol) in dry pyridine (56.5 mL) at 0° C., TsCl (14.9 g, 78.4 mml) was added portion-wise. The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in EtOAc (100 mL) and sequentially washed with 2 N HCl (100 mL), saturated NaHCO3 (100 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to obtain ethyl 3-(tosyloxy)cyclobutanecarboxylate as a pale yellow oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1.[NH2:12][C@H:13]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][N:23]([CH3:24])[C:18]2=[CH:17][C:16]=1[N:25]1[CH2:29][CH2:28][C@H:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]1)[CH3:14].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:15]2[N:20]=[C:19]3[CH:21]=[CH:22][N:23]([CH3:24])[C:18]3=[CH:17][C:16]=2[N:25]2[CH2:29][CH2:28][C@H:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]2)[CH3:14])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CC[C@H](N(C)C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CC[C@H](N(C)C(=O)OC(C)(C)C)C2)c1C#N
Temperature: 90 °C
Yield: 67.8 %

Procedure:
To a 25 mL pear flask were added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (63.4 mg, 0.376 mmol) and tert-butyl ((S)-1-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidin-3-yl)(methyl)carbamate (78 mg, 0.21 mmol) in DMSO (1.0 mL). Triethylamine (146 μL, 1.04 mmol) was added to the mixture, which was then heated to 90° C. for 2 hours. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography (SiO2, 25-100% EtOAc/heptanes gradient) to give the title compound as a foam (72 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.48 (m, 12H), 1.93-2.05 (m, 2H), 2.17-2.30 (m, 4H), 2.92 (s, 3H), 2.97-3.13 (m, 2H), 3.16-3.29 (m, 2H), 3.80 (s, 3H), 4.84 (br s, 1H), 5.71-5.89 (m, 1H), 6.39-6.55 (m, 1H), 6.84 (br s, 1H), 6.96 (d, J=7.58 Hz, 1H), 7.16 (br s, 1H), 7.55 (d, J=3.03 Hz, 1H), 7.85 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:43])[C@H:33](O)[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C@@H:33]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([OH:43])=[O:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](O)CCc1ccccc1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Product: O=C(O)[C@H](CCc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol, and (R)-(−)-2-hydroxy-4-phenylbutyric acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 152-154° C.; MS m/e 537 (M−H)+;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>ClCCl.C1(C)C=CC=CC=1>[C:11]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1)=[O:22])(=[O:19])=[O:18]
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.9 %

Procedure:
13.9 g of 2-amino-4-methoxy-6-methylpyrimidine were dissolved in 150 ml of dry dichloromethane. To this solution was added dropwise a solution of 28.5 g of 2-biphenylylsulfonyl isocyanate in 40 ml of toluene over an hour. During this addition, the internal temperature was maintained at room temperature. When the addition was finished, the mixture was stirred at room temperature for 10 hours to complete the reaction. After completion of the reaction, the mixture was concentrated to about half the volume by evaporating dichloromethane under reduced pressure. The resultant colorless crystals were filtered. The crystals were then washed with a small amount of ether and dried to obtain 34.6 g of N-2-biphenylylsulfonyl-N'-(4-methoxy-6-methylpyrimidin-2-yl) urea; m.p. 199°-202° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:15][C:16]([C:18]2([NH:33]C(=O)OC(C)(C)C)[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:33][C:18]1([C:16]([NH:15][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11][N:12]([CH3:13])[CH3:14])=[O:17])[CH2:19][CH2:20][N:21]([C:24]2[C:25]3[CH:32]=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:22][CH2:23]1
Reactant: CN(C)CCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
Hydrogen chloride (4M in 1,4-dioxane, 1.01 mL, 4.05 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-(dimethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 34) (0.045 g, 0.08 mmol) in a mixture of DCM (5 mL) and methanol (2 mL) at 22° C. The resulting solution was stirred at 22° C. for 16 hours. The mixture was evaporated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-(dimethylamino)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.034 g, 92%) as a colourless gum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:27][CH2:28]2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CN2CCC(C(=O)c3ccc(Cl)cc3)CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (R)4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.5 g, 2.18 mmol) in tetrahydrofuran (15 ml) is added (4-chloro-phenyl)-piperidin-4-yl-methanone (0.49 g, 2.18 mmol) and sodium triacetoxyborohydride (0.69 g, 3.27 mmol), and the reaction mixture stirred for 3.5 hours at ambient temperature. The solvent is evaporated and the residue partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml). The ethyl acetate is dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (ethyl acetate:hexane, 1:1 elution) to afford (S)-4-[4-(4-chloro-benzoyl)-piperidin-1-ylmethyl]-2,2-dimethyl-oxazoldine-3-carboxylic acid tert-butyl ester, [MH]+437.2.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH2:27][CH3:28])[N:25]=[CH:24][CH:23]=2)=[C:12]([F:29])[C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH2:27]([N:26]1[C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][C@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)(=[O:8])=[O:9])=[C:11]([F:30])[C:12]=2[F:29])=[CH:23][CH:24]=[N:25]1)[CH3:28]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1[C@@H]1CCC[C@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Reaction time: 1 h

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (77.2 g, 129 mmol) prepared in Example 118b and triethylsilane (23 mL) in dichloromethane (230 mL), trifluoroacetic acid (230 mL) was added at room temperature, and the reaction solution was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (ethyl acetate/methanol=9:1) to yield the title compound as a colorless solid. A suspension of this title compound in ethyl acetate (200 mL) was further irradiated with ultrasonic wave for 20 minutes. The suspension was filtered, and crystals collected by filtration were washed with ethyl acetate and dried at 40° C. for 24 hours to yield the title compound (44.4 g, 77%) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22](C(OCC)=O)[CH2:21][CH2:20]2)=[CH:5][CH:4]=1.[OH-].[K+].C(O)(C)C>O>[OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: OCc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1
Reaction time: 18 h

Procedure:
Combine (1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (1 mmol), potassium hydroxide (1.2 mmcl), and isopropanol (20 mL). Heat to reflux. After 18 hours, evaporate intcacuo to give a residue. Combine the resczue and water. Extract with dichloromethane. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: C[N:2]([C@@H:19]1[CH2:34][C:33]2=[CH:35][CH:36]=[C:30]([CH:31]=[CH:32]2)[O:29][CH2:28][CH:27]=[CH:26][CH2:25][O:24][CH2:23][C@H:22]([CH:37]([CH3:39])[CH3:38])[NH:21][C:20]1=[O:40])C(=O)OC1C2C=CC=CC=2C2C1=CC=CC=2.C(NCC)C>ClCCl>[NH2:2][C@@H:19]1[CH2:34][C:33]2=[CH:32][CH:31]=[C:30]([CH:36]=[CH:35]2)[O:29][CH2:28][CH:27]=[CH:26][CH2:25][O:24][CH2:23][C@H:22]([CH:37]([CH3:38])[CH3:39])[NH:21][C:20]1=[O:40]
Reactant: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](N(C)C(=O)OC2c3ccccc3-c3ccccc32)C(=O)N1
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3.66 g (6.78 mmol) of 9H-fluoren-9-yl methyl((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18),15-tetraen-12-yl)carbamate (1-1D) in 300 ml of dichloromethane was mixed with 75 ml of diethylamine and stirred at RT for 5 h. The mixture was concentrated and purified by preparative HPLC. Acetonitrile was removed from the combined product fractions in a rotary evaporator, saturated NaHCO3 solution was added, and the mixture was extracted twice with ethyl acetate, saturated with sodium chloride and again extracted with ethyl acetate. The combined ethyl acetate phases were dried over Na2SO4, filtered and concentrated. The resulting substance was pure enough for further reactions.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:18][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
1.04 g (5.0 mmol) of N-(4-nitrophenyl)piperazine was dissolved in 5 ml of dimethylformamide. Sodium hydride (0.24 g, 6.0 mmol) was added to the reaction mixture in three portions under nitrogen atmosphere and cooling over a period of 10 min. After 30 min of stirring, 0.31 ml (6.0 mmol) of methyl iodide was added dropwise to the reaction mixture at 0° C. Stirring was continued for 1 h at room temperature, the reaction mixture was then evaporated to dryness, and purified by silica gel chromatography (methylene chloride:methanol:triethylamine 94:5:1) to yield 1.0 g (90%) of 1-methyl-4-(4-nitrophenyl)piperazine.