Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[Cl:6][C:7]1[CH:8]=[C:9]([CH:14](O)[CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH:10]=[CH:11][C:12]=1[Cl:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([N:2]2[N:3]=[N:4][CH:5]=[N:1]2)[CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: c1nnn[nH]1
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)c(Cl)c2)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(c2ccc(Cl)c(Cl)c2)n2ncnn2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
Tetrazole (90.0 mg, 1.28 mmol) was added to tertiary butyl 3-((3,4-dichlorophenyl)(hydroxy)methyl)azetidine-1-carboxylate (200 mg, 0.638 mmol) and triphenylphosphine (335 mg, 1.28 mmol) dissolved in the distilled tetrahydrofuran solution (15.0 mL), and diisopropyl azocarboxylate (0.25 mL, 1.28 mmol) was slowly added thereto at 0° C., and the mixture was stirred at room temperature for one day. The solvent of the reaction mixture was removed by reduced pressure evaporation to obtain a yellow liquid, which was purified by flash chromatography (n-hexane:ethyl acetate (4:1, v/v)). The product was identified as a single compound by TLC (n-hexane:ethyl acetate (4:1, v/v)) (yield: 88%, white solid). This white solid was dissolved in 10 mL of methanol solution, and 1 N HCl (3.0 mL) was added thereto, and heated to reflux at 60° C. for one day. Thereafter, the solvent of the reaction mixture was removed by reduced pressure evaporation to obtain the title compound (KHG27280).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:35])C.[OH-].[Na+].Cl>C(O)C>[CH:30]1([O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH3:35])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OC3CCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OC3CCCC3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (160 mg; 0.31 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 105 mg (70%). HPLC-MS: m/z: 482.2 (M+H)+; Rt: 1.77 min.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[C:10]([NH:21][C:22]([C:24]3[C:32]4[O:31][CH2:30][O:29][C:28]=4[CH:27]=[CH:26][C:25]=3[Br:33])=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[C:40](N)(=O)C1C=CC=CC=1.[H-].[Na+].CI>CN(C=O)C.CCOCC>[C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[C:10]([N:21]([CH3:40])[C:22]([C:24]3[C:32]4[O:31][CH2:30][O:29][C:28]=4[CH:27]=[CH:26][C:25]=3[Br:33])=[O:23])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1cc2c(NC(=O)c3c(Br)ccc4c3OCO4)ccc(-c3ccc(-c4ccccc4)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2c(-c3ccc(-c4ccccc4)cc3)ccc(N(C)C(=O)c3c(Br)ccc4c3OCO4)c2cc1OC

Procedure:
To a suspension of benzamide N-(4-(biphenyl-4-yl)-6,7-dimethoxynaphthalen-1-yl)5-bromobenzo[1,3]dioxole-4-carboxamide (1 mmol), and NaH (3 mmol) in dry DMF (20 mL) was added MeI (2 equiv). The reaction mixture was stirred over night, diluted with ether and then washed with 10% HCl and brine. The residue was subjected to column chromatography on silica using 2% methanol in chloroform to provide product N-(4-(biphenyl-4-yl)-6,7-dimethoxynaphthalen-1-yl)5-bromo-N-methylbenzo[1,3]dioxole-4-carboxamide as an off white solid. 1H NMR (400 MHz) (CDCl3) δ 3.39-3.60 (m, 3H, N—CH3), 3.66-3.80 (m, 3H, O—CH3), 3.96-4.00 (m, 3H, O—CH3), 5.03-6.18 (m, 2H, O—CH2O), 6.30-7.69 (m, 15H, aromatic).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:60]([C:62]1[CH:63]=[C:64]([CH:87]([CH3:89])[CH3:88])[C:65]2[O:69][C:68]([C:70]3[CH:85]=[CH:84][C:73]([C:74]([NH:76][CH2:77][CH:78]4[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]4)=[O:75])=[CH:72][CH:71]=3)=[N:67][C:66]=2[CH:86]=1)#[N:61]>ClCCl.C(=O)(O)[O-].[Na+]>[C:60]([C:62]1[CH:63]=[C:64]([CH:87]([CH3:89])[CH3:88])[C:65]2[O:69][C:68]([C:70]3[CH:71]=[CH:72][C:73]([C:74]([NH:76][CH2:77][CH:78]4[CH2:83][CH2:82][N:81]([C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=5)[CH2:80][CH2:79]4)=[O:75])=[CH:84][CH:85]=3)=[N:67][C:66]=2[CH:86]=1)#[N:61]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNCC4)cc3)oc12
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)CCNC(=O)OCc5ccccc5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
To a suspension of N-carbobenzoxy-β-alanine (20 mg, 0.090 mmol) in dichloromethane (2 ml) were added o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (65 mg, 0.171 mmol), 1-hydroxybenzotriazole (15 mg, 0.111 mmol), and diisopropylethylamine (0.040 ml, 0.229 mmol). After 5 min, 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-(piperidin-4-ylmethyl)benzamide (30 mg, 0.075 mmol, INTERMEDIATE 15) was added and the mixture was stirred overnight at 25° C. The mixture was diluted with saturated sodium bicarbonate solution (10 ml) and dichloromethane (10 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organics were washed with 10 ml of brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 50% methanol in dichloromethane over 10 column volumes. The resulting mixture was repurified by preparative thin-layer chromatography, eluting with 5% methanol in dichloromethane provide the title compound (24.8 mg, 0.041 mmol, 54.8% yield). Mass spectrum (ESI) 630.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].CCCCCC.C([Li])CCC.[Si:21]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[O:45])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C.C(OCC)C.O1CCCC1>[Si:21]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9])[OH:45])([C:34]([CH3:36])([CH3:37])[CH3:35])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CC(C)(C)[Si](OCCCCCC=O)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCCCCC(O)c1cc(F)ccc1F)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A tetrahydrofuran (30 ml) solution of 1-bromo-2,5-difluorobenzene (0.956 ml, 8.46 mmol) was stirred at −78° C. To the reaction mixture was added a hexane solution (6.46 ml, 10.2 mmol) of n-butyl lithium. The reaction mixture was added to a tetrahydrofuran (20 ml) solution of 6-(t-butyldiphenylsilyloxy)hexanal (2.50 g, 7.05 mmol) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. After the temperature of the reaction mixture was elevated to room temperature, diethyl ether was added thereto. The mixture was washed with a saturated aqueous solution of ammonium chloride and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=9:1 eluate was concentrated under reduced pressure, whereby the title compound (2.92 g, 4.65 mmol, 88%) was obtained as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[CH:9]/[CH2:10]P(OCC)(OCC)=O)=[O:7].[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH:22]=O>C1COCC1>[CH2:4]([O:5][C:6](=[O:7])[CH:8]=[CH:9][CH:10]=[CH:22][C:21]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:20]=1[Cl:19])[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 31 %

Procedure:
To a suspension of 60% NaH in mineral oil (16 g) in 1 L THF was added triethyl 4-phosphonocrotonate (100 g). The resulting solution was stirred for 2 hr, and then a solution of 2,4-dichlorobenzaldehyde (54 g) in 200 mL THF was added thereto. The mixture was stirred at room temperature for 1 hr. The reaction was quenched by the addition of 1 L of aq. NH4Cl and the THF was evaporated. The mixture was extracted with 4×200 ml ethyl acetate and the combined organic layer washed with water, brine and dried over MgSO4 then evaporated to provide the crude product. This was purified by silica gel chromatography using 5% ethyl acetate-hexanes to give 25.9 g of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid ethyl ester. MS: m/e 271.04 (MH+)
Reaction SMILES: [C:1]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[CH:16]=1)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(C1C2C(=CC=CC=2)N(CCCC(OCC)=O)C=1)(=O)CCCCCC>>[C:1]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:16]=1)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12
Agent: CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12
Product: CCCCCCCCCCCCC(=O)c1cn(CCCC(=O)O)c2ccccc12

Procedure:
The procedure of Ex. 2 was repeated except that ethyl 4-(3-tridecanoyl-1-indolyl)butyrate obtained in Ex. 13 was used in place of ethyl 4-(3-heptanoyl-1-indolyl)butyrate to give 4-(3-tridecanoyl-1-indolyl)butyric acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29](I)=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[CH3:35][S:36]([N:39]1[CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41][CH2:40]1)(=[O:38])=[O:37]>>[CH3:32][C:31]1[CH:30]=[C:29]([C:42]2[CH2:41][CH2:40][N:39]([S:36]([CH3:35])(=[O:37])=[O:38])[CH2:44][CH:43]=2)[CH:28]=[C:27]([CH3:34])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(I)cc5C)ccc(F)c43)ccc21
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C6=CCN(S(C)(=O)=O)CC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4-iodo-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described in Step 4 of Intermediate 2. LC (method 8): tR=0.79 min; Mass spectrum (ESI+): m/z=628 [M+Na]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:4]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C1(C)C=CC=CC=1>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]2([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:5]2[N:4]=[C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])[CH:7]=[N:6]2)=[O:30])[N:17]=1
Reactant: NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: N=C(N)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.2 %

Procedure:
To a solution of 1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-cyclopropanecarboxylic acid (582 mg, 1.10 mmol) in DMF (12 mL) at 0° C. was added pyrazole-1-carboxamidine hydrochloride (322 mg, 2.20 mmol) and DIPEA (1.54 mL, 8.80 mmol). After 16 h of stirring at rt, the solution was diluted with toluene (60 mL), causing a dense oil to separate out. The top layer was decanted and the remaining oil was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (240 mg, 37%) as an off-white powder. LCMS: Rt=0.31 min, m/z=572.2 (M+H) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 7.59 (s, 1H), 6.99 (br s, 1H), 5.43 (d, J=5.5 Hz, 1H), 4.91-4.75 (m, 2H assumed; obscured by solvent residual peak), 4.70 (dd, J=8.2, 6.3 Hz, 1H), 4.41-4.34 (m, 2H), 1.20 (br s, 2H), 1.05 (br s, 2H). E-isomer was also obtained. LCMS: Rt=0.33 min, m/z=572.2 (M+H) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 7.58 (s, 1H), 7.46 (br. s., 1H), 5.45 (br. s., 1H), 4.84 (s, 3H), 4.37 (s, 2H), 1.33-1.08 (m, 4H).
Reaction SMILES: [H-].[Na+].C(NC([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)=O)(C)(C)C.[CH2:15]([O:19][C:20]1[C:24](S(C)(=O)=O)=[N:23][S:22][N:21]=1)[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:15]([O:19][C:20]1[C:24]([O:14][CH:12]2[CH2:11][NH:10][CH2:13]2)=[N:23][S:22][N:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(C)NC(=O)N1CC(O)C1
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC1CNC1
Reaction time: 1 h

Procedure:
A suspension of NaH (0.24 g, 0.006 mol) in THF (30 mL) was treated with 1-t-butylcarbamoyl-3-hydroxyazetidine (1.1 g, 0.006 mol), the reaction stirred 1 h, followed by addition of 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0.0042 mol) in THF (5 mL). The reaction was heated to reflux for 4 h, the solvent evaporated, the residue treated with ice-water, and the mixture extracted with EtOAc. The extracts were dried and treated with a slow stream of HCl for 3 min. After 0.5 h, the solvent was evaporated, the residue treated with ice-water, and the solution extracted with ether. The aqueous phase was made basic, extracted with EtOAc, the extracts washed with brine, dried, and the solvent evaporated to give a clear oil. The HCl salt (0.77 g) crystallized from 2-propanol, m.p. 167°-168.5° C. (Compound 50).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].Cl.O1CCOCC1.[CH3:17][C:18]([OH:23])([CH2:21][CH3:22])[CH2:19][CH3:20]>ClCCl>[CH2:19]([C:18]([CH3:17])([O:23][C:2]([NH:1][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])[CH2:21][CH3:22])[CH3:20]
Reactant: CCC(C)(O)CC
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)OC(C)(CC)CC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.500 ml (4.01 mmol) of ethyl isocyanatoacetate was dissolved in dichloromethane. 0.05 ml of 4 N hydrochloric acid/1,4-dioxane solution was added to the obtained solution, and they were stirred at room temperature for 5 minutes. 0.547 ml (4.41 mmol) of 3-methyl-3-pentanol was added to the reaction mixture, and they were stirred overnight. After the concentration under reduced pressure, ethyl acetate was added to the reaction mixture, and they were washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was washed with diethyl ether. The filtrate was concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]2[CH:17]=[CH:18][N:19]=[C:20]([Cl:25])[C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:14])=[O:13])(C)(C)C>C(Cl)Cl>[ClH:25].[NH2:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]2[CH:17]=[CH:18][N:19]=[C:20]([Cl:25])[C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Agent: Cl
Solvent: ClCCl
Product: NCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 198.9 %

Procedure:
A small stream of hydrogen chloride is bubbled through a stirred solution of [2-(1-chloro-isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (6.74 g, 17.5 mmol) in anhydrous CH2Cl2 (100 mL) at 0° C. under nitrogen for 10 minutes. The resultant white suspension is allowed to stir at ambient temperature for 1 hour. After filtration and vacuum drying at 50° C., 5.61 g (17.4 mmol, 100% yield) of the title compound is obtained as a white powder. ESIMS: m/z 286 [(M+H)+, 35Cl], 288 [(M+H)+, 37Cl]. Analysis for C11H13Cl2N3O2S.0.3H2O: calcd: C, 40.33; H, 4.18; N, 12.83; found: C, 40.34; H, 3.80; N, 12.43.
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]=[C:24]([O:28][CH3:29])[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.[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39](O)=[O:40]>>[F:1][C:2]1[CH:3]=[CH:4][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]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:39]([C:31]4[S:30][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=5[N:32]=4)=[O:40])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1nc2ccccc2s1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nc3ccccc3s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and benzo[d]thiazole-2-carboxylic acid (27 mg, 0.15 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.S(Cl)([Cl:15])=O>O>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Solvent: O
Product: O=C(Cl)c1cc(F)c(Cl)cc1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
38.5 g 4-chloro-2,5-difluorobenzoic acid (0.2 mole) was placed in a 250 mL, 3-necked roundbottom flask equipped with a magnetic stirbar, a thermometer, and a water-cooled condenser. 238 g thionyl chloride was added in one lot. The mixture was stirred and heated on a water bath. At about 58°-60° C. the solid dissolved with evolution of gas and formation of foam. The mixture was stirred and maintained at 60° C. until all the solid dissolved - about 30 minutes. It was then heated in a boiling water bath to reflux and held there for 2 hours.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:16][NH2:17])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:18](O)C>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:16][NH2:17])([CH3:15])[C:11]([O:13][CH2:14][CH3:18])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCO
Reactant: COC(=O)C(C)(Cc1ccc(O)c(O)c1)NN
Product: CCOC(=O)C(C)(Cc1ccc(O)c(O)c1)NN

Procedure:
Following the procedure for preparation of compound 107, and substituting methanol with ethanol, provided the title compound, which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:39][C:40]1[C:45]([F:46])=[CH:44][CH:43]=[C:42]([O:47][C@H:48]([CH2:50][CH:51]=[CH2:52])[CH3:49])[C:41]=1B1OC(=O)CN(C)CC(=O)O1.C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(F)C(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C(C)=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:41]5[C:42]([O:47][C@H:48]([CH2:50][CH:51]=[CH2:52])[CH3:49])=[CH:43][CH:44]=[C:45]([F:46])[C:40]=5[F:39])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1ccc(F)c(F)c1B1OC(=O)CN(C)CC(=O)O1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5c(O[C@@H](C)CC=C)ccc(F)c5F)c4)cn23)CC1
Yield: 99 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate and (S)-2-(2,3-difluoro-6-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione in 99% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 702.20.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>[Cu](I)I.C(NC(C)C)(C)C>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)([CH3:26])[CH3:25]
Reactant: Brc1ccc(N(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1ccc(N(c2ccc(C#C[Si](C)(C)C)cc2)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Thereafter, to 200 ml of diisopropylamine were added 15.54 g (0.032 mol of tri(4-bromophenyl)amine, 1.35 g (1.92 mmol) of bis[triphenylphosphin]palladium dichloride and 9.43 g (0.96 mmol) of copper iodide. After the reaction mixture was stirred for 2 h at room temperature, 9.43 g, (96 mmol) of trimethylsilyl acetylene was slowly added to the reaction mixture. The reaction mixture was refluxed for 8 h and cooled. Solvent was removed under the reduced pressure. The residue was extracted with benzene and the benzene layer was washed with distilled water. The washed benzene layer was concentrated to give 13.84 g (81%) of tri(4-trimethylsilylethynylphenyl)amine.