Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:13].[NH2-].[Na+].C1(C)C=CC=CC=1.[CH2:23]([O:25][C:26](=O)[O:27]CC)[CH3:24]>C(OCC)C>[CH2:23]([O:25][C:26](=[O:27])[CH2:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1)[CH3:24]
Reactant: CCOC(=O)OCC
Reactant: COc1ccc2nccc(C)c2c1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccnc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
6-Methoxy-4-methyl-quinoline (0.791 g, 4.572 mmol) was dissolved in anhydrous diethyl ether and cooled to 0° C. under an argon atmosphere. To the stirred mixture was added sodamide as a 50% w/w slurry in toluene (0.36 g, 4.57 mmol). The resulting slurry was allowed to warm to room temperature and was stirred for 1 hour. To this was added diethylcarbonate (0.28 ml, 2.29 mmol). The reaction mixture was then stirred at reflux for 10 hours after which time it was quenched with water (2 ml). The mixture was partitioned between ethyl acetate (2×100 ml) and water (20 ml). The organic phases were combined and dried over magnesium sulfate. The volatiles were removed under reduced pressure and the residue subjected to purification on silica gel using an ethyl acetate-hexane gradient. This provided the desired product as a brown oil (90 mg, 7%).
Reaction SMILES: O1B([C@@H](NC(=O)[C@@H](NC(C2C=NC=CN=2)=O)CC2C=CC=CC=2)CC(C)C)[O:5][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])[O:3]B1[C@@H](NC(=O)[C@@H](NC(C1C=NC=CN=1)=O)CC1C=CC=CC=1)CC(C)C.[C:82](O)(=[O:90])[C@H:83]([C@@H:85]([C:87]([OH:89])=[O:88])[OH:86])O.CCCCCCC>CC(C)=O>[OH:86][C@@H:85]([C@H:83]1[C:82](=[O:90])[O:3][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:35])[CH3:36])[O:5]1)[C:87]([OH:89])=[O:88]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)O1
Solvent: CCCCCCC
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OC(=O)[C@H]([C@H](O)C(=O)O)O1
Yield: 547 %

Procedure:
A mixture of N,N′,N″-(boroxin-2,4,6-triyltris{[(1R)-3-methylbutane-1,1-diyl]imino[(2S)-1-oxo-3-phenylpropane-1,2-diyl]})tripyrazine-2-carboxamide (0.180 g, 0.164 mmol) and D-tartaric acid (147.5 mg, 0.33 mmol) were mixed in acetone (4 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25° C. Heptane (8 mL) was added. The mixture was evaporated to yield (S)-2-hydroxy-2-((S)-2-((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-5-oxo-1,3,2-dioxaborolan-4-yl)acetic acid (0.447 g) which also contained a dimeric species. MS (m/z) in CH3CN: [M+H] calculated for C23H28BN4O8, 499.2000. found, 499.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.CS([Cl:28])(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:28])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(CO)ccc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(CCl)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine methyl 2-methoxy-5-hydroxymethylbenzoate (1.34 g, 6.8 mmol) and N,N-diisopropylethylamine (1.4 mL) in dichloromethane (25 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.56 mL). After 30 minutes, warm to ambient temperature. After 2 hours, dilute with dichloromethane and extract with 1 M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give methyl 2-methoxy-5-chloromethylbenzoate: Rf=0.64 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:42])[NH:38][CH2:39][CH2:40][NH2:41])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:43])[C@@H:9]1[OH:44])([CH3:4])([CH3:3])[CH3:2].[N:46]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=2)[CH2:51][CH2:50][CH:49]([NH:52][C:53](N2C=CN=C2)=[O:54])[CH2:48][CH2:47]1>CC(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:42])[NH:38][CH2:39][CH2:40][NH:41][C:53]([NH:52][CH:49]2[CH2:48][CH2:47][N:46]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=4)[CH2:51][CH2:50]2)=[O:54])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:43])[C@@H:9]1[OH:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of {(1S,2R,3S,4R)-4-[2-(2-amino-ethylcarbamoyl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-carbamic acid tert-butyl ester (2.5 g, 4.05 mmol) in IPA (10 ml) is added imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (Intermediate C) (151 ml of a 10 mg/ml solution in DCM, 5.56 mmol) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the crude product is purified by chromatography on silica eluting with DCM/MeOH (25:1 increasing to 15:1). The resulting solid is further purified by dissolving in DCM and washing the solution with water, drying (MgSO4) and concentrating in vacuo to afford the title product. (MH+ 820.7)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[C:5]2([CH3:16])[CH3:15].[OH:17][CH:18]([CH3:22])[C:19](O)=O.N>Cl>[CH2:12]([N:7]1[C:8]2[CH:9]=[C:10]3[N:11]=[C:19]([CH:18]([OH:17])[CH3:22])[NH:1][C:2]3=[CH:3][C:4]=2[C:5]([CH3:15])([CH3:16])[C:6]1=[O:14])[CH3:13]
Reactant: CC(O)C(=O)O
Reactant: CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Agent: Cl
Agent: N
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(C(C)O)nc3cc21
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
A mixture of 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (10 g, 46 mmol), 2-hydroxy-propionic acid (9.13 g, 91.2 mmol) in HCl (100 mL, 4N) was refluxed for 16 h. After cooling, neutralization with aqueous ammonia (25%) and stirring for 1.5 h the precipitate was filtered and dried in vacuo at 50° C. yielding 12.29 g (95%) of a grey solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Product: COc1cccc(-c2ocnc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27]N4C5C=CC=CC=5N=N4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:45]1[C:53]2[CH:52]=[CH:51][CH:50]=[C:49](O)[C:48]=2[CH:47]=[CH:46]1.CN(C)C=O>C(#N)C>[CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:49]4[CH:50]=[CH:51][CH:52]=[C:53]5[C:48]=4[CH:47]=[CH:46][NH:45]5)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]2)[CH2:4][O:3]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(On2nnc3ccccc32)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2cccc3[nH]ccc23)cc1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84.6 %

Procedure:
A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Example 109, Step 1, 0.25 g, 0.47 mmol) in acetonitrile (10 mL, 0.048M) was treated with cesium carbonate (0.31 g, 0.95 mmol) and 1H-indol-4-ol (75.4 mg, 0.56 mmol). The resulting reaction mixture was stirred at 25° C. for 3.5 h. At this time, the reaction was treated with N,N-dimethylformamide (1.0 mL) and the reaction was heated at 80° C. overnight. The reaction mixture was then concentrated in vacuo and partitioned between water (75 mL) and ethyl acetate (75 mL). The emulsified bilayer was filtered through filter paper and rinsed with water and ethyl acetate. The layers were separated, and the organics were washed with a saturated aqueous sodium chloride solution (50 mL). The combined aqueous layers were acidified with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 24 g, 1-10% methanol/methylene chloride) afforded 2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (207.1 mg, 81%) as a viscous brown/black oil as a mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][OH:15])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]2)[CH:3]=1.[CH2:29]([NH2:33])[CH2:30][CH2:31][NH2:32]>>[NH2:32][CH2:31][CH2:30][CH2:29][NH:33][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][OH:15])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]2)[CH:3]=1
Reactant: NCCCN
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OCCO)ccc3n2)Cc2ccccc21
Product: NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(OCCO)cc12
Temperature: 150 °C
Yield: 35.8 %

Procedure:
A mixture of 2-{[4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinolin-6-yl]oxy}ethanol (250 mg, 0.6 mmol) and propane-1,3-diamine (88.8 mg, 1.2 mmol) was heated for 1.5 hours at 150° C. under microwave irradiation. The reacting mixture was purified by preparative HPLC and SPE to afford 98.2 mg of the desired product (yield was 35.8%). MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.02 (d, J=8 Hz, 1 H), 7.88-7.80 (d, J=7.6 Hz, 1 H), 7.77-7.68 (q, J=9.6 Hz, 2 H), 7.60-7.50 (m, 2 H), 7.42-7.38 (m, 1 H), 5.94 (s, 1 H), 5.29 (s, 2 H), 4.55-4.42 (m, 2 H), 4.18-4.10 (t, J=4.4 Hz, 2 H), 3.90-3.85 (t, J=4.4 Hz, 2 H), 3.76-3.68 (t, J=4.4 Hz, 2 H), 3.62-3.55 (t, J=6.8 Hz, 2 H), 3.12-3.05 (t, J=7.6 Hz, 2 H), 2.15-2.00 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)=[O:17])=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(CCNC(=O)OC(C)(C)C)cc2)CC1

Procedure:
4-(2-Tert-butoxycarbonylamino-ethyl)-benzoic acid was reacted with WSCI, HOBt, triethylamine and N-methylpiperazine in dichloromethane, to obtain a crude product of {2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester, and then treated with TFA, to obtain [4-(2-amino-ethyl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and [4-(2-amino-ethyl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone (39 mg) instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine used in Step D in Example 1-D-18, in the same manner as Step D in Example 1-D-18, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-amide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-294) as a colorless powder (121 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([CH:10]=O)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:14][NH2:15].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([CH2:10][NH:15][CH3:14])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1c(C=O)sc2ccc(Cl)cc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1sc2ccc(Cl)cc2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-chloro-3-methyl-benzo[b]thiophene-2-carbaldehyde (5.10 g, 24.2 mmol) was added a solution of 2 M methylamine in methanol (81 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue taken up in ethanol (81 mL). The solution was cooled to 0° C., NaBH4 (1.37 g, 36.3 mmol) was added in one portion, and stirring was continued overnight. The mixture was concentrated under reduced pressure and the residue was combined with 1 M NaOH (200 mL). The mixture was extracted with diethyl ether (3×150 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to the title compound (4.83 g, 88%) as a pale yellow oil which crystallized under vacuum: 1H NMR (300 MHz, CDCl3) δ 7.69-7.59 (m, 2H), 7.25 (m, 1H), 3.96 (s, 2H), 2.50 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=O)=O>Cl.O.C(O)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:11]
Reactant: O=C(O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(Br)c(S)c1
Temperature: 80 °C

Procedure:
A suspension of stannous chloride dihydrate (21 g, 93.1 mmol) in hydrochloric acid and water (25 mL, 4:1, v/v) was added dropwise with stirring to a solution of Example 1a (5.0 g, 16.7 mmol) in glacial acetic acid (57 mL) at 80° C. The reaction mixture was heated for 1 h at 80° C. and treated with ice-water to obtain a mixture of the title compound and its dimer as a white solid, which was washed with water and dried. Yield: 3.2 g, (82%); mp: 315-317° C.; MS: m/e (EI+) 233 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[CH:15]=1.CCN=C=NCCCN(C)C.[C:37]([S:41]([NH2:44])(=[O:43])=[O:42])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:37]([S:41]([NH:44][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][C:16]=12)=[O:24])(=[O:43])=[O:42])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (170 mg, 0.49 mmol) in dry DCM (10 mL) was added EDCI (288 mg, 1.5 mmol) followed by DMAP (0.18 g, 1.4 mmol) and stirring was continued at 25° C. for 2 h. To the reaction mixture was added tert-butyl sulfonamide (67 mg, 0.49 mmol) and the stirring was continued at 25° C. for 72 h. Reaction mixture was diluted with DCM (50 mL) and the organic layer was washed with saturated aqueous KHSO4 solution followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by combiflash chromatography followed by re-crystalisaiton from EtOH to afford (R)-N-(tert-butylsulfonyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide as white solid. MS (ESI): m/z 463.2 (M+H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)=[O:3].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.N1C=CC=CC=1>[N:20]1([C:2]([C:4]2[CH:19]=[CH:18][C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)=[CH:6][CH:5]=2)=[O:3])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: C1CCNC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
4-(4-Chlorocarbonylbenzyl)-nitrobenzene was dissolved in dichloromethane (40 mL) and a solution of pyrrolidine (64 mg, 1 eq) in pyridine (0.2 mL) was added. The mixture was stirred for 2 hours at room temperature, washed with dilute potassium hydroxide, and solvents evaporated to yield a yellow oil. The residue was chromatographed on silica gel, eluting with dichloromethane/methanol, to give 4-(4-pyrrolidin-1-ylcarbonylbenzyl)-nitrobenzene (299 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[C@H:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=2[CH3:21])=[O:33])=[CH:27][CH:26]=1
Reactant: Cc1ccc([C@@H]2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: COc1ccc(CC(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CC(=O)Nc2c(C)c(C)c3c(c2C)[C@@H](c2ccc(C)cc2)C(C)(C)O3)cc1
Yield: 74 %

Procedure:
Using (+)-(3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 134 and -4-methoxyphenylacetic acid, the title compound was synthesized in the same manner as in Reference Example 359. Yield 74%. Melting point: 186-188° C. (ethyl acetate-hexane).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[CH:23][CH:22]=3)=[CH:15]2)=[C:11]([F:37])[CH:10]=1>CO>[ClH:8].[Cl:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[CH:15]=[C:16]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH:17]=[CH:18][C:19]2=[O:20])=[C:11]([F:37])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 178 %

Procedure:
According to Scheme 19 Step 2: HCl/dioxane (10 eq, 4M, 5.00 mL) was added to a solution of tert-butyl 4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenylcarbamate (1 eq, 2.00 mmol, 1.00 g) in MeOH (20 mL) at 0° C. The reaction was stirred for 2 days at 80° C., then the solvent was concentrated and Et2O was added. The solid was filtered and dried to yield 1-(4-chloro-2-fluorobenzyl)-5-(4-aminophenyl)pyridin-2(1H)-one hydrochloride (1.78 mmol, 0.76 g, 89%) as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].C(N(CC)CC)C.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[Cl:47])[CH2:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:42]([NH:41][CH2:40][C:39]2[CH:44]=[CH:45][C:46]([Cl:47])=[C:37]([Cl:36])[CH:38]=2)=[O:43])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.17 g, 0.42 mmol) and triethylamine (0.12 mL, 0.86 mmol) were combined in CH2Cl2 (2 mL). 3,4-Dichlorobenzyl isocyanate (0.08 mL, 0.52 mmol) was added, and the reaction was stirred at room temperature for 15 minutes. After concentrating, the crude material was purified by silica gel chromatography (20-50% EtOAc in hexanes) to give {2′-[3-(3,4-dichloro-benzyl)-1-ethyl-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester. The ethyl ester was hydrolyzed according to the procedure described in Example 23, Step 2.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[C:15]([Si:19]([CH3:34])([CH3:33])[O:20][CH:21]1[C:30]2[C:25](=[C:26]([CH:31]=O)[CH:27]=[CH:28][CH:29]=2)[O:24][CH2:23][CH2:22]1)([CH3:18])([CH3:17])[CH3:16].[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClC(Cl)C>[C:15]([Si:19]([CH3:33])([CH3:34])[O:20][CH:21]1[C:30]2[C:25](=[C:26]([CH2:31][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=[CH:28][CH:29]=2)[O:24][CH2:23][CH2:22]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OC1CCOc2c(C=O)cccc21
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC1CCOc2c(CN3CCCCC3)cccc21
Reaction time: 1 h

Procedure:
NaBH(OAc)3 (3.86 g, 18.21 mmol) was added to a dichloroethane (30 mL) solution of 4-(tert-butyl-dimethyl-silanyloxy)-chroman-8-carbaldehyde (2.66 g, 9.10 mmol) and piperidine (2.70 mL, 27.31 mmol) at RT. After stirring for 1 h, the reaction was quenched with MeOH (10 mL) while the stirring was continued for 20 more min. The reaction was diluted with CH2Cl2 (200 mL) and washed with saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo from heptane to provide the title compound.