Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13]Br)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:37][O:38][CH2:39][C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][N:41]3[CH2:42][CH2:43][CH2:44][C@H:40]3[CH2:39][O:38][CH3:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COC[C@@H]1CCCN1
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC[C@@H]1CCCN1CCCc1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn12
Temperature: 55 °C
Yield: 65.9 %

Procedure:
1-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Example 193 step 1) (50 mg, 0.088 mmol) and (2S)-2-(methoxymethyl)pyrrolidine (36 uL, 0.263 mmol) were added to a vial. DMF was added (1 mL) followed by triethylamine (15 uL, 0.109 mmol) and KI (spatula tip). The vial was capped and the reaction heated at 55° C. for two hours. Upon cooling the product precipitated out of solution. The solids were collected by filtration and rinsed with ether to yield 35 mg (65%) of clean product. 1H-NMR (DMSO-d6) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.55 to 7.21 (m, 4H), 6.57 (s, 1H), 3.32 (s, 3H), 3.18 to 2.83 (m, 7H), 2.37 to 1.45 (m, 5H); MS [M+H]+=604.2; LCMS RT=2.59
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:25])[CH2:13][CH:14]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[S:15]1)[CH3:10].Br[CH2:27][C:28]([OH:30])=[O:29].Cl>C1COCC1.C(OCC)C>[C:28]([CH2:27][N:18]1[C:19](=[O:20])[CH:14]([CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:25])[S:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]1=2)([OH:30])=[O:29]
Reactant: CCOC(=O)CC1Sc2ccccc2NC1=O
Reactant: O=C(O)CBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC1Sc2ccccc2N(CC(=O)O)C1=O
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of LDA (2M) in THF (3.26 mmol) in 2 mL of anhydrous THF at 0° C. and under nitrogen, a solution of (3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid ethyl ester (1.62 mmol) in 4 mL of dry THF is added dropwise. The temperature of the reaction mixture is held at room temperature for 2 hours and then dropped to −78° C. A solution of 2-bromo acetic acid (1.64 mmol) in 2 mL of anhydrous THF is added and the temperature of the reaction is slowly let to rise to room temperature. HCl (1M) is added to reach pH=1. Ethyl ether is added and the phases are separated. The organic phase is dried on Na2SO4, the drying agent is filtered and the solvent evaporated. The crude product is purified by automated column chromatography (hexane/EtOAc) to give the product ethyl 2-(3,4-dihydro-4-(carboxymetyl)-3-oxo-2H-benzo[b][1,4]thiazin-2-yl)acetate. Yield: 50%. 1H NMR (400 MHz, CDCl3): δ 9.07 (bs, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 4.69 (dd, 2H), 4.18 (dd, 2H), 3.99 (t, J=6.4 Hz, 1H), 3.04 (dd, J1=6.4 Hz, J2=16.8 Hz, 1H), 2.58 (dd, 1H), 1.26 (m, 3H).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH:25]=[C:24]([CH2:26][OH:27])[N:23]=[CH:22]1.C(N(CC)CC)C>CN(C=O)C>[C:1]([N:21]1[CH:25]=[C:24]([CH2:26][OH:27])[N:23]=[CH:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Trityl chloride (45.57 g, 0.163 mol), (1H-imidazol-4-yl)-methanol (20.00 g, 0.148 mol) and triethylamine (37.46 g, 0.370 mol) in DMF (150 mL) are stirred at r.t. for 16 h, whereupon the mixture is poured into ice-cold water. The precipitate is filtered off and dried under high vacuum to give (1-trityl-1H-imidazol-4-yl)-methanol as a solid. Crude (1-trityl-1H-imidazol-4-yl)-methanol (26.4 g, 0.077 mol), imidazole (15.88 g, 0.233 mol), DMAP (0.950 g, 7.7 mmol) and TBSCl (12.89 g, 0.085 mol) in DMF (0.1 L) are stirred at r.t. for 2 h, whereupon water is added. The mixture is extracted three times with dichloromethane. The organic layer is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel flash chromatography (elution with hexanes-ethyl acetate, 7:3) to yield 4-(tert-butyl-dimethyl-silanyloxymethyl)-1-trityl-1H-imidazole as a white solid; MS (ESI) m/z 243, 455 (M+H).
Reaction SMILES: [CH2:1]=[C:2]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.CC[O-].[Na+]>CS(C)=O>[CH:13]1[C:14]2[CH:2]([CH2:1][CH:26]3[C:27]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:20]4[C:25]3=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: C=C1c2ccccc2-c2ccccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)-c1ccccc1C2CC1c2ccccc2-c2ccccc21
Temperature: 90 °C
Yield: 28.1 %

Procedure:
A mixture of dibenzofulvene (1 g, 5.68 mmol), fluorene (0.93 g, 5.68 mmol) and EtONa (0.19 g, 2.79 mmol) in DMSO (20 mL) was heated at 90° C. for 16 hours, and was then cooled to room temperature. After carrying out the work-up, as reported in Example 8, 0.55 g of bis(9-fluorenyl)methane were obtained, with a yield of 28%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 99 %

Procedure:
4-Fluoro-2-methyl-1-nitrobenzene (2 g), piperazine-1-carboxylic acid tert-butyl ester (4.8 g), potassium carbonate (3.57 g) and dimethyl sulfoxide (20 ml) were heated together at 80 ° C. under nitrogen for 15 h. The mixture was then cooled, diluted with ethyl acetate (200 ml), washed with 2N aqueous hydrochloric acid (200 ml), dried (MgSO4), and concentrated to give the subtitle compound (4.10 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([CH2:16][OH:17])[CH2:12][C@H:11]([OH:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:19](C1NC=CN=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([CH2:16][O:17][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:12][C@H:11]([OH:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)c1ncc[nH]1
Reactant: C=C1[C@H](CO)C[C@H](O)C[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)C[C@H](O)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
The compound of Example 16H (574 mg, 2.1 mmol) was dissolved in 35 mL of dichloromethane and tert-butyldimethylsilylimidazole (0.54 mL, 2.8 mmol) was added. After stirring overnight, the reaction was diluted with dichloromethane and washed twice with 10% NaCl, then dried over MgSO4, filtered and concentrated in vacuo. After a second run using 340 mg of the starting diol, the combined unpurified product mixtures were purified by silica gel chromatography (200 mL of SiO2, elution with a gradient of 1:4 ethyl acetate:hexanes to ethyl acetate) to afford the titled compound (940 mg) contaminated with a small amount of a regioisomeric bis-TBS ether.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[C:14]([CH2:15][CH2:16][NH:17][C:18]([C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]3)=[O:19])=[CH:13][N:12]=[CH:11]2)=[CH:7][CH:6]=1)#[N:4].CCN(CC)CC.[C:35]1([CH:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[BH3-]C#N.[Na+]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:14]([CH2:15][CH2:16][NH:17][C:18]([C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][N:21]3[CH2:42][CH:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:19])=[CH:13][N:12]=[CH:11]2)=[CH:26][CH:27]=1)#[N:4]
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2CCCCN2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2CCCCN2CC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Piperidine-2(S)-carboxylic acid {2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide dihydrochloride (0.503 mmol) was dissolved in MeOH (3 mL) and the pH of the solution adjusted to 5 with Et3N. 2,2-Diphenylacetaldehyde (0.267 mL, 1.508 mmol) and NaCNBH3 (0.095 g, 1.508 mmol) were added, and the reaction mixture stirred for 18 hr at ambient temperature. The mixture was concentrated to remove the MeOH, then partitioned between CH2Cl2 and aq satd NaHCO3 solution. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to give the title compound after SiO2 chromatography eluting with CH2Cl2 : MeOH, NH4OH, 98:1.8:0., and conversion to the hydrochloride salt.
Reaction SMILES: [CH:1]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].N1C=CC=CC=1.[OH2:21].CC(C)=[O:24]>>[C:13]([OH:12])(=[O:14])[C:3]1[C:4](=[CH:5][C:6](=[CH:1][CH:2]=1)[C:7]([OH:24])=[O:8])[C:10]([OH:11])=[O:21]
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)OC2=O
Reactant: CC(C)=O
Reactant: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc(C(=O)O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
Trimellitic acid anhydride chloride (32.40 g, 0.154 mol) was dissolved 100 mL acetone in a 3-neck flask under nitrogen. The flask was cooled in an ice bath. The solution was stirred continuously while a solution of AFM-1 (35.25 g, 0.0773 mol), and pyridine (12.32 g, 0.154 mol) in 50 ml of acetone was added slowly to the cold solution using a dropping funnel. After addition was completed, the flask contents were continuously stirred at room temperature for 4 hours. Water (2.77 g, 0.154 mol) was added and stirring at room temperature was continued overnight. Then the solid formed was removed by vacuum filtration and washed with acetone. The filtrate was concentrated and dried to a white solid with 73% yield. The structure confirmed by NMR.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]2[C:20](=[O:21])[C:19](=[O:22])[NH:18][C:15]2=[N:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:20]([OH:21])([C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=3[O:9][CH3:10])[C:19](=[O:22])[NH:18][C:15]2=[N:16][CH:17]=1
Reactant: COc1ccc(C)cc1Br
Reactant: O=C1Nc2ncc(Cl)cc2C1=O
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ncc(Cl)cc21
Yield: 81.9 %

Procedure:
With 1.49 g of 2-bromo-4-methyl anisole and 900 mg of the compound obtained in Step 118-4 as starting materials, 1.23 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[I-].[K+].[NH3:35].C(N(C(C)C)CC)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:35][S:46]([CH3:45])(=[O:48])=[O:47])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: N
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNS(C)(=O)=O)CC2)nc1N
Reaction time: 6 h
Yield: 26 %

Procedure:
A suspension of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (210 mg, 0.43 mmol, Example 272), potassium iodide (200 mg, 1.2 mmol) and ammonia (1.5 mL, 7M in methanol, Aldrich) was heated at 100–110° C. in a sealed tube with stirring for 6 hours. Solvent was removed and the crude amine product was dissolved in tetrahydrofuran (12 mL). The resulting solution was cooled to 0–5° C., treated with diisopropylethylamine (200 mg, 2.0 mmol, Aldrich) and then with a bolus of methanesulfonyl chloride (100 mg, 0.88 mmol, Aldrich). After stirring at ambient temperature for 3 hours, the solution was washed with 10% NaHCO3. The organic layer was separated and dried (Na2SO4). The residue was purified by silica gel chromatography (5% methanol/methylene chloride) and precipitated from tetrahydrofuran/ethyl ether to give N-(3-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonyl]-propyl)-methanesulfonamide as a white solid (60 mg, 26% yield). HRMS, observed: 445.1652; Calcd for (M+H)+: 445.1647
Reaction SMILES: [F:1][C:2]([F:18])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:3]([O:5]CC)=[O:4].CO.[OH-].[Na+:22]>O>[F:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([F:18])[C:3]([O-:5])=[O:4].[Na+:22]
Reactant: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])C(F)(F)c1ccc2ncccc2c1

Procedure:
8.1 g (32.2 mmol) of ethyl difluoro(quinolin-6-yl)acetate was added to a reaction balloon. Methanol (40.5 mL) and water (2.9 mL) were added. To this solution, 1.29 g sodium hydroxide (32.2 mmol) was added at room temperature for 16 h. The resulting solids were filtered off and dried under vacuum. Yield 4.5 g (18.4 mmol; 57%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH:17]([CH2:19][OH:20])[OH:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:28][C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1CCC(N=C=NC2CCCCC2)CC1.CCOC(C)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH:17]([CH2:19][O:20][C:33](=[O:34])[C@H:29]([CH:30]([CH3:31])[CH3:32])[NH:28][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[OH:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)CO
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 49 %

Procedure:
1-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (17.95 g. 61.6 mmol), Boc-L-valine (6.69 g, 30.8 mmol), DMAP (0.38 g, 3.1 mmol), and DCC (7.10 g, 34.4 mmol) in 240 mL CH2Cl2 and 60 mL DMF were stirred at rt under N2 for 18 h. The EtOAc. The organic solution was washed with 50 mL saturated NH4Cl. The aqueous phase was reextracted with 50 mL EtOAc. The organic phases were combined, washed successively with 50 mL saturated NaHCO3 and 50 mL brine, dried over Na2SO4, and concentrated under vacuum. Flash column chromatography of the crude material on silica gel (eluent 2/1 petroleum ether—EtOAc, and then EtOAc) gave 7.41 g (49%) of the title compound (alternative nomenclature: 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propanol).
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=O.[C:20]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:4]1[CH:3]([CH:1]=[CH:27][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2
Reactant: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Solvent: C1CCOC1
Product: CCCCCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 0 °C
Yield: 92.2 %

Procedure:
A mixture of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [6 g; prepared as hereinbefore described in Example 1(iv)] and hexanoylmethylenetriphenylphosphorane (8.5 g.) in dry tetrahydrofuran (50 ml.) was heated to reflux under nitrogen for 16 hours. The solvent was removed in vacuo and the residue triturated with petroleum ether (b.p. 60°-80° C.), cooled to 0° C. for 1 day, filtered to remove triphenylphosphine oxide and the filtrate evaporated. The residue was again triturated with petroleum ether (b.p. 60°-80° C.) to remove further triphenylphosphine oxide, filtered, and evaporated to give 6-(7-hydroxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (7.5 g.), νmax 1620 cm-1, 1660 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13][Mg]Br>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH:7]([OH:8])[CH3:13])[CH:9]=1
Reactant: COc1c(C)cc(F)cc1C=O
Reactant: C[Mg]Br
Solvent: CCOCC
Product: COc1c(C)cc(F)cc1C(C)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a stirred solution of 5-Fluoro-2-methoxy-3-methylbenzaldehyde (1.2 g, 7.13 mmol) in dry diethyl ether (20 mL) at 0° C. was added methylmagnesium bromide of 3.0 M in ether (6.0 mL, 17.83 mmol). The reaction mixture was brought to room temperature and was stirred for 30 min. then refluxed for 3 h. It was then cooled to 0° C. and quenched by adding saturated aqueous NH4Cl. The two liquid layers were separated. The aqueous layer was extracted with ether. The combined organic layers were washed with water, dried, and concentrated to the crude compound which was purified by silica gel column (10-25% ethyl acetate in hexanes) to afford 1-(5-fluoro-2-methoxy-3-methylphenyl)ethanol (1.0 g, 76%): 1H NMR (400 MHz, CDCl3): δ 7.12 (dd, 1H), 6.83 (dd, 1H), 4.72 (m, 1H), 3.81 (s, 3H), 2.38 (s, 3H), 1.47 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]1([C:27]#N)[CH2:26][CH2:25][CH2:24]1.C1C[O:32]CC1>>[CH3:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]1([C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:32])[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1c(C2(C#N)CCC2)nc2ccccc21
Reactant: C1CCOC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Product: Cn1c(C2(C(=O)c3ccccn3)CCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
To a solution of 2-bromopyridine (449 mg, 2.84 mmol) in THF (10 mL) was added dropwise n-butyl lithium (1.6 N, 1.77 mL, 2.84 mmol) at −78° C. After stirring at the same temperature for 30 minutes, a solution of Example 275B (400 mg, 1.89 mmol) in THF (2 mL) was added. The mixture was stirred at −78° C. for additional 30 minutes and then quenched with aqueous H2SO4 solution (1 N, 5 mL) slowly. The reaction mixture was warmed up to room temperature and partitioned. The aqueous phase was separated and extracted with EtOAc (3×10 mL). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (430 mg, 0.50 mmol, 26.4% yield) as a yellow solid. MS: MS (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([NH2:14])[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1>O1CCCC1>[C:4]([NH:14][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH3:3].[C:2]([CH2:3][C:4]([NH:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])=[O:5])(=[O:6])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: Nc1cccc(N)c1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)Nc1cccc(NC(=O)CC(C)=O)c1
Product: CC(=O)Nc1ccccc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 87.6 %

Procedure:
168 g of diketene were slowly added to a solution of 108 g of m-phenylenediamine in a liter of tetrahydrofuran and the mixture was stirred for 5 hours at 20° C. and then was allowed to stand for 15 hours. The mixture was concentrated to dryness under reduced pressure and the residue was added to methanol. The mixture was vacuum filtered and the recovered precipitate was dried to obtain 180 g of m-(acetylacetamido)-acetyl-acetanilide acetanilide melting at 117° C. Chromatography over silica gel and elution with a 6- 4 methylene chloride-acetone mixture gave a product melting at 118° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5](N)[CH:4]=1)#[N:2].Cl.N([O-])=[O:13].[Na+].C1(C)C=CC=CC=1>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([OH:13])[CH:4]=1)#[N:2]
Reactant: O=N[O-]
Reactant: Cc1ccc(C#N)cc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)cc1O
Reaction time: 20 h
Yield: 68.8 %

Procedure:
Into a reaction vessel was charged 4-cyano-2-aminotoluene (13) (132.0 g, 1.0 mol) and 6 N hydrochloric acid aqueous solution (800 ml), and an aqueous solution obtained by dissolving ice-cooled sodium nitrite (76.0 g, 1.1 mol) in water (320 ml) was dropped over 1.5 hours, further, the solution was stirred for approximately 20 hours under ref lux. To the reaction liquid was added toluene and extracted, then, a sodium hydroxide aqueous solution was added to the toluene layer to make the aqueous layer alkaline. The resulted aqueous layer was acidified with concentrated hydrochloric acid, then, extracted with ethyl acetate. The resulted ethyl acetate layer was washed with saturated saline, dried, and the solvent was distilled off under reduced pressure, to obtain 4-cyano-2-hydroxytoluene (14) (91.6 g, yield from (13) is 69%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:25][CH2:24][CH2:23][C:12]=4[N:13]=[C:14]([N:16]4[CH2:19][CH2:18][C@H:17]4[C:20]([OH:22])=O)[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1.[F:26][C:27]1[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.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>CN(C=O)C.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:25][CH2:24][CH2:23][C:12]=4[N:13]=[C:14]([N:16]4[CH2:19][CH2:18][C@H:17]4[C:20]([NH:33][C:30]4[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:22])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)nc1
Reactant: O=C(O)[C@@H]1CCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)nc1)[C@@H]1CCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
To a solution of (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)azetidine-2-carboxylic acid (300 mg, 0.909 mmol) in DMF (3 mL) was added 6-fluoropyridin-3-amine (203 mg, 1.818 mmol), HATU (414 mg, 1.091 mmol) and DIPEA (0.26 mL, 1.45 mmol). The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with water (8×30 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 40 mg of (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamide as the formate salt. 1H NMR (400 MHz, CD3OD, TFA salt) δ (ppm): 0.40-0.60 (m, 2H), 0.70-0.85 (m, 2H), 1.58-1.70 (m, 1H), 2.20-2.37 (m, 2H), 2.58-2.69 (m, 1H), 2.79-2.97 (m, 3H), 2.98-3.06 (m, 2H), 4.21-4.38 (2H), 5.16 (dd, 1H), 6.16 (s, 1H), 7.05 (dd, 1H), 8.05-8.17 (m, 1H), 8.30 (s, 1H). The other enantiomer was prepared using the (R) chiral starting material.