Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:17][OH:18])[O:4][C@H:5]2[N:9]1[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]1=[O:11].[CH3:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([C:25](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([O:18][CH2:17][C@@:3]23[C@@H:2]([OH:1])[C@@H:6]([O:7][CH2:8]2)[C@H:5]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:4]3)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:24]2[CH:41]=[CH:42][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=c1ccn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4ccc(=O)[nH]c4=O)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 44 (0.08 g, 0.31 mmol) in anhydrous pyridine (0.5 cm3) was added 4,4′-dimethoxytrityl chloride (0.203 g, 0.6 mmol) at 0° C. and the mixture was stirred at room temperature for 2 h. The reaction was quenched with ice-cold water (10 cm3) and extracted with dichloromethane (3×4 cm3). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogencarbonate (3×3 cm3) and brine (2×3 cm3) and was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 45 as a white solid material (0.12 g, 69%). δH (CDCl3) 9.25 (1H, br s, NH), 7.93 (1H, d, J 7.2, 6-H), 7.50-7.15 (9H, m, DMT), 6.88-6.78 (4H, m, DMT), 5.63 (1H, s, 1′-H), 5.59 (1H, d, J 8.0, 5-H), 4.48 (1H, s, 2′-H), 4.26 (1H, s, 3′-H), 3.88 (1H, d, J 8.1, 1″-Ha), 3.85-3.55 (7H, m, 1″-Hb, OCH3), 3.58-3.40 (2H, m, 5-Ha, 5′-Hb). δC (CDCl3) 164.10 (C-4), 158.60 (DMT), 150.45 (C-2), 147.53 (DMT), 144.51 (C-6), 139.72, 135.49, 135.37, 130.20, 129.28, 128.09, 127.85, 127.07 (DMT), 113.39, 113.17 (DMT), 101.79 (C-5), 88.20, 87.10, 86.87 (C-1′, C-4′, DMT), 79.25, 71.79, 69.70, 58.13 (C-2′, C-3′, C-5′, C-1″), 55.33 (OCH3). FAB-MS m/z 559 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)=[O:4].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:15]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=2)=[O:4])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: c1nc[nH]n1
Reactant: CCCOc1ccc(C(=O)CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCOc1ccc(C(=O)Cn2cncn2)cc1
Yield: 30.4 %

Procedure:
By substantially following the procedure of Example 608a using 29 g of 2-bromo-4'-propoxyacetophenone (Example 585b), 10 g of 1,2,4-triazole, 15 g (116 mmole) of diisopropylethylamine, and 100 ml of tetrahydrofuran, 8.4 g of the desired compound, mp 97°-99° C., was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10](=[N:16]O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:28][C:27]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:30][CH:29]=3)=[N:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(N(C)C)cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(N(C)C)cc1
Yield: 32.9 %

Procedure:
Ethyl 3-(4-dimethylaminophenyl)-2-hydroxyimino-3-oxopropionate (3.8 g) and 4-nitrobenzylamine (2.8 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-dimethylaminophenyl)-2-(4-nitrophenyl)-imidazole-4-carboxylate (1.8 g), melting point 240-242° C.
Reaction SMILES: C([O:6][CH2:7][CH:8]([OH:11])[CH2:9]Cl)(=O)C(C)=C.[C:12]1([C:18]2[NH:22][N:21]=[N:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na]>COCCO>[OH:11][CH:8]([CH2:7][OH:6])[CH2:9][N:22]1[C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][N:20]=[N:21]1
Reactant: C=C(C)C(=O)OCC(O)CCl
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: [Na]
Solvent: COCCO
Product: OCC(O)Cn1nnnc1-c1ccccc1
Temperature: 100 °C

Procedure:
A solution of 3-chloro-2-hydroxypropyl methacrylate (0.50 mole; 89.3 g. and 500 ppm 4-methoxyphenol as inhibitor) in 2-methoxyethanol (300 ml) was added to sodium 5-phenyltetrazole (1.0 mole; 168.2 g) dissolved in 2-methoxyethanol (800 ml) and heated at 100° C. for 14.5 hours. The product solution was quenched with H2O (150 ml), extracted with CH2Cl2 (3×500 ml), the extracts washed with H2O (500 ml) and concentrated to a semi-solid, m.p. 25°-115° C, gas evolution, 219° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[N:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:31])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1cnc(C(F)(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3cnc(C(F)(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-trifluoromethyl-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a colorless oil. MS (ISP): m/z=434.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.I[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:24][CH2:25][CH2:26][CH3:27])[C:8]=2[N:9]=1
Reactant: CCCCI
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a suspension of NaH (60% in mineral oil, 34 mg) in 6 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (202 mg, 0.66 mmol). The mixture was heated to 50° C., resulting in a clear solution. 1-Iodobutane (105 μL, 0.92 mmol) was added, and the solution was stirred at 50° C. for 30 minutes, then cooled to room temperature and poured onto 40 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The residue was dried and purified by flash chromatography, eluting with a gradient of 1:1 hexane:ethyl acetate to all ethyl acetate to provide 152 mg (64%) of 2-amino-8-butyl-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp 202°-205° C.
Reaction SMILES: C([O:5][NH:6][C:7]([C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[S:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])=[O:8])(C)(C)C>ClCCCl>[OH:5][NH:6][C:7]([C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[S:15]([N:18]1[CH2:19][CH2:20][CH:21]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)(=[O:17])=[O:16])=[O:8]
Reactant: CC(C)(C)ONC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCCl
Product: O=C(c1ccc(Cl)cc1)C1CCN(S(=O)(=O)N2CCCC[C@@H]2C(=O)NO)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (100 mg, 0.22 mmol), [prepared as described in Step 1 above], in 1,2-dichloroethane (10 ml) was cooled to −30° C. and HCl gas was bubbled through it for 10 min. The reaction vessel was then sealed and stirred at RT. After 2 days, the reaction mixture was vented with nitrogen and then concentrated in vacuo. The residue was chromatographed (PTLC, SiO2, 10% methanol/methylene chloride) to give N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide as a white solid (5 1%), mp 84.4-86.4° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([C:22]([O:24]CC)=[O:23])=[C:15]4[N:14]=3)[C@@:11]([CH2:28][OH:29])([CH3:27])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]4[N:14]=3)[C@@:11]([CH2:28][OH:29])([CH3:27])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3[C@@H](c4cncc(F)c4)CC[C@@]3(C)CO)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@]1(CO)CC[C@H](c2cncc(F)c2)N1c1ccn2ncc(C(=O)O)c2n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.1 %

Procedure:
A mixture of ethyl 5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (52.0 mg, 0.130 mmol) and NaOH (26.0 mg, 0.325 mmol) in MeOH (1.0 mL) was stirred at ambient temperature for 60 hours. The reaction was treated with HCl (4 N dioxane, 163 μL, 0.651 mmol) and concentrated. The residue was treated with DCM and filtered through Celite. The solution was concentrated to afford 5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (29 mg, 60% yield) as a white solid. MS (apci) m/z=372.0 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:5]=2[S:4](=[O:19])[CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([OH:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:5]=2[S:4](=[O:19])[CH2:3]1
Reactant: CN1CS(=O)c2cc(C(=O)c3ccccc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CS(=O)c2cc(C(O)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
0.02 mol of 3-methyl-6-benzoylbenzothiazolinone prepared in Example 2 are dissolved, with magnetic stirring, in 200 cm3 of methanol in a 250 cm3 flask. 0.04 mol of sodium borohydride is added very slowly, with agitation. The agitation is maintained for 4 hours at ambient temperature. The reaction medium is evaporated under vacuum on a water bath The residue is taken up in water, and the precipitate formed is drained and dried.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: Cc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--see Preparation 8), 4-methylphenethyl bromide (0.44 g), anhydrous potassium carbonate (0.6 g) and acetonitrile (20 ml) was heated under reflux for 1.25 hours. The mixture was partitioned between 10% aqueous potassium carbonate (10 ml) and dichloromethane (20 ml), the layers were separated, and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.32 g.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24]2)[C:8]2[NH:13][N:12]([C@@H](C3C=CC=CC=3Cl)C)[NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C@H:57](O)[CH3:58]>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:28])([F:29])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11]([C@H:57]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=3[Cl:50])[CH3:58])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1Cl)N1Nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2N1
Reactant: C[C@@H](O)c1ccccc1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: C[C@@H](c1ccccc1Cl)n1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-2-[(R)-1-(2-chloro-phenyl)-ethyl]-7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 87), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-1-(2-chlorophenyl)ethanol and isolated as light-yellow gum (3.8 mg, 21%). MS(m/e): 421.4 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:4][N:5]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14]([CH:22]=[O:23])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1F)[CH:10]=2)[CH3:2].[F:37][C:38]([F:44])([CH:41]([F:43])[F:42])[CH2:39][OH:40].[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:4][N:5]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14]([CH:22]=[O:23])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:40][CH2:39][C:38]([F:44])([F:37])[CH:41]([F:43])[F:42])[CH:10]=2)[CH3:2]
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)c3ccccc3F)cc2c2cc(C=O)c3ccccc3c21
Reactant: OCC(F)(F)C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c2ccc(C(=O)c3ccccc3OCC(F)(F)C(F)F)cc2c2cc(C=O)c3ccccc3c21
Temperature: 70 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To 11-(2-ethylhexyl)-8-(2-fluorobenzoyl)-11H-benzo[a]carbazole-5-carbaldehyde (1.73 g, 3.60 mmol) in pyridine (18 ml) are added 2,2,3,3-tetrafluoropropanol (0.72 g, 5.48 mmol) and sodium hydroxide (0.24 g, 6.00 mmol) at room temperature. The reaction mixture is heated at 70° C. After stirring for 3 hours, the reaction mixture is poured into ice-water. The crude product is extracted with CH2Cl2 and washed with water and brine. After drying over MgSO4 and concentration, the product is reprecipitated from hexane and ethylacetate to obtain an off-white solid (1.91 g, 89%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.83-0.89 (m), 1.19-1.51 (m), 2.26 (m), 4.32 (t), 4.72 (m), 5.29 (t), 7.03 (d), 7.26 (t), 7.56-7.61 (m), 7.69-7.78 (m), 8.07 (d), 8.58 (d), 8.60 (s), 8.61 (s), 10.39 (s); 19F-NMR spectrum (CDCl3). δ [ppm] −140.92, −126.30.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N12CCCC=C1CCNC[CH2:14]2.S(OC)(OC)(=O)=O.Cl>C(#N)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: C1=C2CCNCCN2CCC1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: Cl
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(Cl)cc(C)c1N
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a suspension of 2-amino-5-chloro-3-methylbenzoic acid (i.e. the product of Step A) (92.8 g, 500 mmol) in acetonitrile (500 mL) at 0-5° C. was added 1,4-diaza-bicyclo[5.4.0]undec-7-ene (DBU, 90 mL, 92 g, 600 mmol), and then dimethyl sulfate (57 mL, 76 g, 600 mmol) was added dropwise at 0-5° C. After stirring 3 h at this temperature, additional DBU (15 mL) and dimethyl sulfate (10 mL) were added. After stirring another 3 h at this temperature, more additional DBU (15 mL) and dimethyl sulfate (10 mL) were added. After stirring another 2 h at this temperature, concentrated hydrochloric acid (60 mL, 720 mmol) was added dropwise at 0-10° C. The resulting suspension was stirred for 30 minutes at 0-5° C., then filtered, and the solids were washed with ice-cold 2:1 water-acetonitrile (3×100 mL), and dried under nitrogen. The crude product was suspended in methanol (250 mL), water (1000 mL) was added, and the mixture was stirred at room temperature for 1 h. Then the solids were filtered, washed with 4:1 water-methanol (100 mL), then with water (3×100 mL), and dried under nitrogen to afford the title compound as a low-melting white solid, 87.6 g (87.8% yield). HPLC of the solid product showed 99.7 area % of the title ester.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Cl)[CH:9]=2)[C:3]=1[C:15]([NH2:17])=O.FC(F)[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][C:22]=1O>CCO.N1CCCCC1>[C:3]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4]2[NH:5][N:6]=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=3)[C:3]=2[C:15]#[N:17])=[CH:9][CH:10]=1)([CH3:15])([CH3:4])[CH3:2]
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1ccc(Nc2[nH]nc(N=Cc3ccc(O)cc3)c2C#N)cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 4-(difluoromethoxy)-3-hydroxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[CH2:9](O)[CH2:10][CH2:11][CH2:12][OH:13]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O:5][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH3:2]
Reactant: OCCCCO
Reactant: CCP(=O)(O)CCO
Solvent: Cc1ccccc1
Product: CCP(=O)(CCO)OCCCCO
Yield: 79.9 %

Procedure:
414 g (3.0 mol) of ethyl(2-hydroxyethyl)phosphinic acid (produced as in Example 7) are at 80° C. dissolved in 400 ml of toluene and admixed with 594 g (6.6 mol) of 1,4-butanediol and esterified at about 100° C. in a distillation apparatus equipped with water trap during 4 h. On completion of the esterification the toluene is removed in vacuo to leave 504 g (80% of theory) of 4-hydroxybutyl ethyl-(2-hydroxyethyl)phosphinate as colorless oil.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[CH3:24][N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:31](=[O:32])[CH2:30][C:26]1[N:25]([CH3:24])[CH:29]=[CH:28][CH:27]=1
Reactant: Cn1cccc1CC(=O)O
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cccc1CC(=O)N1CCc2c1ccc(-c1cn(C)c3ncnc(N)c13)c2F
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
A solution of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (100 mg, 0.281 mmol), (1-methyl-1H-pyrrol-2-yl)acetic acid (39.1 mg, 0.281 mmol), HATU (107 mg, 0.281 mmol), and DIEA (0.245 mL, 1.404 mmol) was stirred at room temperature for 3 days. The resulting suspension was poured into water (10 mL) and stirred for 30 min, and a precipitate formed. The precipitate was collected by filtration, and the residue was washed with water, then dried at the pump for an hour, then adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 5-{4-fluoro-1-[(1-methyl-1H-pyrrol-2-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (70 mg, 61.7% yield) as an off-white solid. LC-MS (ES) m/z=405 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25 (t, J=8.34 Hz, 2H), 3.54 (s, 3H), 3.69-3.79 (m, 3H), 3.87 (s, 2H), 4.33 (t, J=8.34 Hz, 2H), 5.82-5.95 (m, 2H), 5.95-6.19 (m, 2H), 6.69 (t, J=2.27 Hz, 1H), 7.16-7.24 (m, 1H), 7.26 (s, 1H), 7.93 (d, J=8.08 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][CH2:29][CH2:30]O)([CH3:21])[CH3:20])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:37][CH2:30][CH2:29][CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]([NH:18][C:14]1[C:13](=[O:32])[N:12]([C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([F:34])[C:9]=2[CH3:33])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:35])[CH:17]=[CH:16][N:15]=1)([CH3:21])[CH3:20]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2CCCO)c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2CCCBr)c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-[3-({1-[2-(3-hydroxypropyl)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide (Example 323h) (0.4 g) dissolved in THF (10 mL) was treated with carbon tetrabromide (0.277 g) under nitrogen. The resulting mixture was cooled to 0° C. before adding triphenylphosphine (0.219 g). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated and the residue purified (SiO2 chromatography eluting with 50% DCM in ethyl acetate) to give the subtitle compound as a solid (0.135 g). 1H NMR δ (CDCl3) 7.65-7.56 (m, 1H), 7.55-7.46 (m, 1H), 7.43-7.34 (m, 1H), 7.26-7.17 (m, 4H), 6.80-6.71 (m, 1H), 6.64-6.55 (m, 1H), 3.38 (t, 2H), 3.08-2.82 (m, 3H), 2.14 (s, 3H), 1.91 (d, 6H), 1.29-1.18 (m, 2H), 0.91-0.81 (m, 2H), 0.66-0.55 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:33])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[S:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.OO.Cl([O-])=[O:37].[Na+]>C(#N)C.C(OCC)(=O)C>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:33])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:27][C:28]([C:31]([OH:37])=[O:32])=[CH:29][CH:30]=2)=[CH:24][CH:25]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C=O)s2)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)O)s2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-(5-formyl-2-thienyl)phenyl]ethyl]-carbamate (180 mg) in acetonitrile (2 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1 ml) was added 30% hydrogen peroxide solution (30 μl) and 80% sodium chlorite (67 mg) below 10° C. The reaction mixture was stirred at 50° C. for 3 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 5-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-2-thiophenecarboxylic acid (160 mg).