Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[OH:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[OH:25])=[C:11]([C:40]3[CH2:41][CH2:42][O:37][CH2:38][CH:39]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (R)—((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-tert-butylphenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@H:29]([OH:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[OH:39][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[N:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=C1N=C(N2CCCCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and 4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; mp>85° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H), 2.55-2.95 (m, 6 H), 3.60 (br s, 2 H), 3.70-3.95 (m, 6 H), 6.66 (d, J=9.0 Hz, 2 H), 6.75 (d, J=9.0 Hz, 2 H), 7.02 (d, J=9.0 Hz, 1 H), 7.48 (d, J=9.0 Hz, 1 H), 7.50 (s, 1 H), 8.90 (brs, 1 H); MS (ES) m/z: 269.0 ((M+2H)2+, 100%); 537.6 (MH+, 10%); HRMS Calcd. for C29H37N4O4S (MH+): 537.2536. Found: 537.2500.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH2:4].[C:5]([C:8]1[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])(=O)[CH3:6]>O>[OH2:3].[CH3:6][C:5]1[C:8]2[C:9](=[CH:13][C:14]([CH3:18])=[C:15]([CH3:17])[CH:16]=2)[C:10](=[O:11])[O:12][C:2]=1[C:1]([OH:4])=[O:3]
Reactant: CCO
Reactant: CC(=O)c1cc(C)c(C)cc1C(=O)O
Solvent: O
Product: Cc1cc2c(C)c(C(=O)O)oc(=O)c2cc1C

Procedure:
4,6,7-Trimethylisocoumarin-3-carboxylic acid monohydrate, mp. (EtOH-H2O) 241°, (Found: C, 62.27; H, 5.74 C13H12O4. H2O requires C, 62.39; H, 5.64) was prepared from 2-acetyl-4,5-dimethylbenzoic acid by an analogous procedure to that described in Example 2.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[N:5][N:6]([CH3:13])[C:7]=1[N:8]=[CH:9]OCC)#[N:2].[CH3:22][NH2:23]>C(O)C>[CH3:22][NH:23][C:1]1[N:2]=[CH:9][N:8]=[C:7]2[N:6]([CH3:13])[N:5]=[C:4]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:3]=12
Reactant: CCOC=Nc1c(C#N)c(-c2ccc([N+](=O)[O-])o2)nn1C
Reactant: CN
Solvent: CCO
Product: CNc1ncnc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C

Procedure:
A mixture of 10.0 grams of 4-cyano-5-ethoxymethyleneamino-1-methyl-3-(5-nitro-2-furyl)-pyrazole, and 100 milliliters of a 33 % solution of methylamine in ethanol was heated at reflux for 30 minutes and cooled. The crystalline solid precipitated was collected, washed with ether and dried. Recrystallisation from dimethylformamide gave 4-methylamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, having melting point 280°C.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:27][CH2:28][CH2:29][CH2:30][S:31](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:33])=[O:32]>>[Cl:27][CH2:28][CH2:29][CH2:30][S:31]([NH:21][CH2:20][CH:19]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:33])=[O:32]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CN)NC(=O)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)OC

Procedure:
3-Hexadecylthio-2-methoxycarbonylaminopropylamine IVe3 is allowed to react and worked up by the same procedure as described in (4). m.p. 67°-69° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)=[CH:4][CH:3]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][NH:27][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Sc2ccc(Cl)cc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Clc1ccc(Sc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 75A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[N:27]([CH2:28][C:29]3[S:33][C:32]4[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:31]=4[CH:30]=3)[C:17]3=[CH:18][N:19]=[C:20]([O:22][CH2:23][CH2:24][O:25]C)[CH:21]=[C:16]3[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])[CH3:3].B(Br)(Br)Br.Cl>C(Cl)Cl>[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[N:27]([CH2:28][C:29]3[S:33][C:32]4[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:31]=4[CH:30]=3)[C:17]3=[CH:18][N:19]=[C:20]([O:22][CH2:23][CH2:24][OH:25])[CH:21]=[C:16]3[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])[CH3:3]
Reactant: COCCOc1cc2cc(C(=O)NC3CCN(C(C)C)CC3)n(Cc3cc4ccc(Cl)cc4s3)c2cn1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2cc3cc(OCCO)ncc3n2Cc2cc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 810 mg (1.236 mmol) of 1-(6-Chloro-benzo[b]thiophen-2-ylmethyl)-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide hydrochloride in 80 mL CH2Cl2 2.472 mL of a 1M solution of BBr3 in CH2Cl2 were added. The mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo and lyophilized. The residue was purified by preparative HPLC (eluent: CH3CN/H2O/0.1% CF3COOH). The fractions containing the product were combined, concentrated in vacuo and lyophilized with 2.5 equivalents of 1N HCl yielding the hydrochloride salt of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]2)=[CH:4][C:5]([NH:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:21][C:22]1[CH:36]=[CH:35][C:25]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24][C:23]=1[N:37]=[C:38]=S.CC(C)N=C=NC(C)C>>[Cl:21][C:22]1[CH:36]=[CH:35][C:25]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24][C:23]=1[NH:37][C:38]1[N:9]([CH3:10])[C:5]2[CH:4]=[C:3]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([F:19])([F:20])[F:18])[CH2:13][CH2:12]3)[C:2]([Cl:1])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The sub-title compound was prepared in analogy to Example 76 using 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (508 mg, 1.65 mmol), tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate (493 mg, 1.65 mmol), DIC (208 mg, 1.65 mmol) and
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:28][CH:29]([Cl:33])[C:30](Cl)=[O:31]>>[Cl:28][CH:29]([Cl:33])[C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)C(Cl)Cl)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and dichloroacetyl chloride (22 mg, 150 μmol). Yield 20 mg (83%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=3)[CH:21]=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[OH:36][N:35]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(c2cccc(-c3cccc(C(=O)O)c3)c2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(-c3cccc(C(=O)O)c3)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (8.5:1) as an off-white solid, MS (ESI+): m/z=451.20 ([M+H]+).
Reaction SMILES: O[CH2:2][C:3]([CH2:13][OH:14])([CH2:10][CH2:11][CH3:12])[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].C(=O)(OCC)OCC.[OH-].[K+]>C(O)C>[OH:9][CH:4]([C:3]1([CH2:10][CH2:11][CH3:12])[CH2:2][O:14][CH2:13]1)[C:5]([F:6])([F:7])[F:8]
Reactant: CCCC(CO)(CO)C(O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: CCCC1(C(O)C(F)(F)F)COC1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A mixture of 3,3-di-(hydroxymethyl)-1,1,1-trifluorohexan-2-ol (2.8 g.), diethyl carbonate (1.6 ml.), potassium hydroxide (0.1 g) and dry ethanol (4.0 mls) was refluxed gently (oil bath 110°), under a current of nitrogen, for 30 minutes. The ethanol was then removed by distillation. Distillation gave 3-(1-hydroxy-2,2,2-trifluoroethyl)-3-n-propyloxetane (1.7 g.), a colourless oil (b.p. 112°, 20-25 m.m).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and pyrrolidine.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:35]=[C:34]([N+:36]([O-])=O)[CH:33]=[CH:32][C:8]=1[O:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:21][CH2:20]2)=[O:18])[CH:11]=1.[H][H]>[C].[Pd].CO>[NH2:36][C:34]1[CH:33]=[CH:32][C:8]([O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:21][CH2:20]3)=[O:18])[CH:11]=2)=[C:7]([F:6])[CH:35]=1
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCN(CCN2CCCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 4.5 h
Yield: 81.6 %

Procedure:
After adding tetrahydrofuran (3 ml) and methanol (3 ml) to a crude product of 4-[2-(pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (129 mg) under a nitrogen atmosphere, 10% palladium-carbon (60 mg) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 4.5 hours. The atmosphere in the reaction vessel was then replaced with nitrogen, and the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=19:1), and then Fractions containing the target compound were concentrated under reduced pressure to provide a crude product of the title compound (98.4 mg) as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH:15]1[CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([N:15]2[CH2:17][CH2:16]2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: C1CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
13.0 g (55.6 mmol) of 4-[(methylsulfonyl)amino]benzoyl chloride is suspended in 150 mL of methylene chloride and cooled to about 0° C. 2.40 g (55.7 mmol) of aziridine and 7.75 mL (55.6 mmol) of triethylamine are added and the reaction allowed to warm to room temperature and stir for 2 hours. After 2 hours, the solution is washed with 100 mL of saturated aqueous sodium chloride and placed in the freezer. After 18 hours, the resulting white precipitate is filtered, washed with 50 mL of ether and dried to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([S:35]([N:38]3[CH2:43][CH2:42][NH:41][CH:40]([CH2:44][CH3:45])[CH2:39]3)(=[O:37])=[O:36])[S:32][C:31]=2[CH:46]=1.[Cl-].[NH4+]>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:41]2[CH2:42][CH2:43][N:38]([S:35]([C:33]3[S:32][C:31]4[CH:46]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=4[CH:34]=3)(=[O:37])=[O:36])[CH2:39][CH:40]2[CH2:44][CH3:45])=[O:10])=[N:4][CH:3]=1
Reactant: CCC1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1
Reactant: O=C(O)c1ncc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1C(=O)c1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N,N-dimethylformamide (0.15 ml) was added to a methylene chloride solution (25 ml) of 5-bromopyrimidine-2-carboxylic acid (455 mg) was added and the resulting mixture was ice cooled. Oxalyl chloride (564 mg) was added and the resulting mixture was stirred for 30 minutes under ice cooling. The resulting solution, together with diisopropylethylamine (2.7 ml), was added to a methylene chloride solution (25 ml) of 1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-3-ethylpiperazine (255 mg), followed by stirring at 0° C. for 1 hour. The reaction mixture was added successively with a saturated aqueous solution of ammonium chloride and distilled water. The water layer was extracted three times with methylene chloride. The organic layers were combined, washed three times with distilled water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:100), whereby the title compound (308 mg) was obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].CCN(C(C)C)C(C)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[C:21](Cl)=[O:22]>O1CCOCC1>[OH:4][CH2:3][CH:2]([NH:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([N+:27]([O-:29])=[O:28])=[C:18]([O:17][CH3:16])[CH:19]=1)[CH2:5][OH:6]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: NC(CO)CO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC(CO)CO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 2-amino-propane-1,3-diol (1 equiv) in 1,4-dioxane (0.062 M) was added DIEA (2 equiv) and a solution of 3-methoxy-4-nitrobenzoyl chloride (1 equiv) in 1,4-dioxane (1.86 M) dropwise at room temperature. The resulting mixture was stirred at room temperature for 15 min. The solution was concentrated and the crude material was triturated in a 5:1 mixture of water:DCM (0.5 M), filtered, and dried to afford the title compound the solid (85% yield) that was used in the next step without further purification. MS (ESI) m/z 271.1 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[N+:10]([CH3:13])([O-:12])=[O:11].[O-]CC.[Na+].C(O)C.C(O)(=O)C>C(O)C>[N+:10]([CH2:13][C:3]1([OH:9])[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)([O-:12])=[O:11]
Reactant: O=C1CN2CCC1CC2
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
A mixture of 3-quinuclidinone (24.4 g, 0.195 mole) and nitromethane (15.9 g, 0.260 mole) in absolute ethanol (100 ml) was added to a cooled (0° C.) mechanically stirred solution of 21% sodium ethoxide/ethanol (64.8 g, 200 mole) in absolute ethanol (300 ml) under nitrogen. The mixture was stirred at room temperature for one hour, then at 55°(±5°) C. for 18 hours. The cooled suspension was treated dropwise with acetic acid (13.2 g, 0.220 mole), filtered through Celite®, washed with methanol, and concentrated in vacuo. The residue was filtered through alumina (eluted with 1:2 methylene chloride/methanol), concentrated in vacuo, and triturated from acetonitrile to afford 8.44 g (23%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[N:4]([C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:20]=[CH:19][N:18]=2)[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=2)=[C:5]([CH3:16])[N:4]([C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1Oc1ccc(CO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of {4-[3,5-dimethyl-1-(4-pyridin-2-yl-pyrimidin-2-yl)-1H-pyrazol-4-yloxy]-phenyl}-methanol (1.53 g, 4.10 mmol) in chloroform (80 mL) was added the Dess-Martin periodinane (2.36 g, 5.56 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated to provide a white paste. Flash chromatography over silica (methanol/methylene chloride) provided 1.37 g (90%) the product as a white solid. 1H NMR analysis was consistent with assigned structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][C@H:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]2=[O:9].[BH4-].[Na+]>CCO>[OH:9][CH:6]1[C@@H:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C@H:3]2[CH2:8][C@@H:7]1[C:2]2([CH3:1])[CH3:16]
Reactant: CCOC(=O)C[C@H]1C[C@H]2C[C@@H](C1=O)C2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C[C@H]1C[C@H]2C[C@@H](C1O)C2(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a cooled solution of Example 23A (0.62 g, 2.8 mmol) in EtOH (20 mL) was added sodium borohydride (0.13 g, 3.3 mmol) in portions at 0° C. The mixture was stirred at 0° C. for 4 hours and at room temperature overnight. The reaction mixture was then cooled, quenched with 1M NaHCO3, extracted with dichloromethane (3×15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-30% of ethyl acetate in hexanes) to obtain 0.35 g of the title compound. MS (DCI/NH3) m/z 244 (M+NH4)+
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:23][CH:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1.[C:36]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[F:35][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH:22]([N:24]([CH3:36])[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(NS(C)(=O)=O)C2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(N(C)S(C)(=O)=O)C2)n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
To a solution of compound N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamide (Example 30) (182 mg, 0.36 mmol) in DMF (4 mL) was added dry powdered K2CO3 (1.0 g, 7.3 mmol) and iodomethane (0.5 mL, excess). The reaction mixture was stirred at 20° C. for 20 hrs and diluted with water. The resulting precipitate was collected by filtration, washed with water, and dried. Recrystallization from CH2Cl2/MeOH gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-N-methylmethanesulfonamide in 83% yield: mp (CH2Cl2/MeOH) 290-291; 1H NMR (DMSO-d6) δ7.99 (d, J=7.8 Hz, 1H), 7.75 (t, JHF=53.0 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 4.78-4.71 (m, 1H), 4.46-4.26 (m, 4H), 3.98 (s, 3H), 3.80-3.79 (m, 4H), 3.69 (m, 4H), 2.93 (s, 3H), 2.91 (s, 3H); Anal. Calcd. for C21H26F2N8O4S: C, 48.1; H, 5.0; N, 21.4. Found: C, 47.9; H, 4.9; N, 21.5%.
Reaction SMILES: N.[Si:2]([O:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH2:17][N:18]2[CH2:34][CH2:33][C:21]3([O:26][CH2:25][CH2:24][N:23](C(=O)C(F)(F)F)[CH2:22]3)[CH2:20][CH2:19]2)[S:15][CH:16]=1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]>CO>[Si:2]([O:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH2:17][N:18]2[CH2:34][CH2:33][C:21]3([O:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH2:20][CH2:19]2)[S:15][CH:16]=1)([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1
Agent: N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCc1csc(CN2CCC3(CC2)CNCCO3)c1

Procedure:
‘880’ Aqueous ammonia (1.5 mL) was added to stirred solution of 1-(9-((4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2,2,2-trifluoroethanone (example 43, step a) (1.0 g) in methanol (5 mL). After 16 h the reaction mixture was evaporated to dryness. Acetonitrile was added, the solution evaporated to dryness in vacuo, and this process was repeated three times to give the subtitled compound as a white solid. Yield 0.78 g.