Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:35]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:36])[CH2:31][CH2:30]1)(=[O:28])=[O:27])[CH:20]=[CH:19]2>C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:30][CH2:31][N:32]([C:35]([CH:37]3[CH2:42][CH2:41][N:40]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][N:3]=4)[CH2:39][CH2:38]3)=[O:36])[CH2:33][CH2:34]1)(=[O:27])=[O:28])[CH:20]=[CH:19]2
Reactant: O=C(C1CCNCC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: Clc1ccncn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(C1CCN(c2ccncn2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Yield: 60.8 %

Procedure:
4-Chloropyrimidine (1.72 g) and triethylamine (5.3 ml) were added to a solution of 4-(1-(6-chloronaphth-2-ylsulphonyl)piperazin-4-ylcarbonyl)piperidine (4 g) in ethanol (100 ml) and the mixture heated on a steam bath overnight. The mixture was cooled to give a precipitate which was collected to filtration and recrystallised from acetonitrile to give 1-(6-chloronaphth-2-ylsulphonyl)-4-[1-[4-pyrimidinyl]piperidin-4-ylcarbonyl]piperazine (2.88 g); mp 218-219° C.;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[OH:20]OS([O-])=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:5]2[N:11]=[C:10]([C:12]([OH:20])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=S([O-])OO
Reactant: O=Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1

Procedure:
2-Chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carbaldehyde (0.56 g) was reacted with Oxone (1.1 eq) in DMF (10 mL) overnight. The DMF was removed under vacuum and the reaction mixture was brought up into water. The pH was adjusted to 2-3 and product crashed out of solution. The solid was collected by filtration and dried to afford 0.45 g of 2-chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxylic acid as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.I[CH:15]([CH3:17])[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH:15]([CH3:17])[CH3:16])[C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC1(C)Cn2c(cc(Cl)nc2=O)N1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1c2cc(Cl)nc(=O)n2CC1(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To a solution of 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (400 mg, 2.00 mmol) and 2-iodopropane (375 mg, 2.20 mmol) in acetonitrile (7 mL) was added Cs2CO3 (1.31 g, 4.01 mmol). The reaction mixture was stirred at 90° C. for 2 h, filtered and concentrated. Purification via MDAP afforded the title product (40 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:33]1[CH2:36][CH:35]([NH:37]C(=O)OC(C)(C)C)[CH2:34]1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.CC(O)C>[NH2:37][CH:35]1[CH2:36][N:33]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:13][CH:14]=3)=[O:7])=[CH:4][N:3]=2)[CH2:34]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: NC1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 70 mg, 0.143 mmol), tert-butyl azetidin-3-ylcarbamate (49.4 mg, 0.287 mmol), DIPEA (0.075 mL, 0.430 mmol) and iPrOH (1 mL) in a sealed vial was stirred at 120° C. for 2 h. The RM was treated with sat. aq. Na2CO3, extracted with EtOAc and the combined extracts were washed with brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 97:3). Fractions containing the desired intermediate were combined and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in DCM (1 mL), treated with TFA (0.216 mL, 2.80 mmol) and stirred at RT for 3 h. The RM was treated with sat. aq. Na2CO3, and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 11). Fractions containing the product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a white solid. HPLC (Condition 7) tR=5.545 min, UPLC-MS (Condition 3) tR=0.77 min, m/z=435.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.05 (m, 2H) 3.35-3.35 (m, 2H) 3.53-3.69 (m, 1H) 3.80-3.96 (m, 2H) 6.34-6.45 (m, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.74 (br. s, 1H) 7.87 (d, J=8.99 Hz, 2H) 8.00-8.10 (m, 1H) 8.66-8.78 (m, 1H) 10.24 (br. s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[N:27]1[N:28]=[C:29]([NH:32][CH:33]2[CH2:38][CH2:37][CH:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:35][CH2:34]2)[NH:30][CH:31]=1.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:18])[N:32]([C@H:33]3[CH2:34][CH2:35][C@H:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:37][CH2:38]3)[C:29]3[N:28]([N:27]=[CH:31][N:30]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCOC(=O)C1CCC(Nc2nnc[nH]2)CC1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)OCC)CC2)c2ncnn12
Temperature: 180 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.5 g), ethyl 4-(4H-1,2,4-triazol-3-ylamino)cyclohexanecarboxylate (0.68 g) and N,N-diethylaniline (2.5 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.23 g, 31%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=O)=[CH:15][S:14][C:13]1=[N:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=O)(C)(C)C.[Cl:34][C:35]1[CH:42]=[CH:41]C(CBr)=[CH:37][CH:36]=1.Cl>>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([CH2:17][O:19][CH2:20][C:21]2[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=2)=[CH:15][S:14][C:13]1=[N:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:25][CH:24]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCOC(=O)c1csc(=Nc2ccc(OC(F)(F)F)cc2)n1CCCNC(=O)OC(C)(C)C
Agent: Cl
Product: NCCCn1c(COCc2ccc(Cl)cc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Yield: 50.4 %

Procedure:
The compound (313 mg) obtained in Example 208 (2) and 4-chlorobenzyl bromide (216 mg) were treated in a similar manner to in Example 208 (3), (4) to give the title compound (152 mg) as hydrochloride.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:5]1([CH2:4][O:3][C:1](=[O:2])[NH:11][CH:12]([CH3:13])[C:14](=[O:16])[NH:17][N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nn1cccc1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nn1cccc1
Reaction time: 20 h
Yield: 66 %

Procedure:
To a stirred solution consisting of carbobenzyloxy-D,L-alanine (10.0 g) and N-aminopyrrole (3.68 g) in dry DCM (224 ml) was added DCC (9.71 g) at room temperature under nitrogen. After stirring for 20 hours, the reaction mixture was filtered through a pad of celite and the solid DCU was washed with DCM. Concentration of the filtrate gave the crude product. Purification via flash column chromatography (silica gel, 30% ethyl acetate/hexane) afforded 8.50 g of the product as a solid, m.p. 153°-155° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][CH3:73]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:72][CH3:73])[CH:66]=1)#[N:69]
Reactant: COc1cc(C#N)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Br)ccc32)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 92 (0.4 g, 0.66 mmol), was reacted with diisopropylethylamine (0.77 g, 5.9 mmol), diphenylphosphinic chloride (0.62 g, 2.6 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.29 g, 2.0 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a off white solid (Yield 0.15 g, 36%).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([NH:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cn1cc(-c2cc3c(-c4cccc(NC5CCNCC5)n4)n[nH]c3cn2)cn1
Yield: 5.4 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 4-aminopiperidine-1-carboxylate were reacted and the product was deprotected to give 200 as a white solid (5.4% over two steps). 1H NMR (400 MHz, MeOD) δ 8.97 (s, 1H), 8.61 (s, 1H), 8.47 (s, 2H), 8.12 (s, 1H), 8.01 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.44 (d, J=7.3 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 4.69 (m, 1H), 4.41-4.32 (m, 1H), 3.99 (s, 3H), 3.52-3.43 (m, 2H), 3.12 (dd, J=16.9, 6.7 Hz, 2H), 2.44-2.33 (m, 2H), 1.97-1.85 (m, 2H). LC/MS: m/z 375.1 [M+1]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](O)=[O:8].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([Cl:15])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1cccc(F)c1
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1cccc(F)c1
Yield: 94.7 %

Procedure:
A mixture of trans 3-fluorocinnamic acid (32.3 g), thionyl chloride (48 g) and dry benzene (300 ml) was heated at reflux for 2 hours. Solvent and excess thionyl chloride was removed by distillation at reduced pressure leaving trans 3-fluorocinnamoyl chloride (34 g) as the oil.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:18][NH2:19])=[O:17])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:20][O:21][C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)=[O:23]>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([NH:18][NH:19][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:32][CH:31]=2)=[O:17])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(CCC(=O)NN)cc1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCOc1ccc(CCC(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a suspension of 3-(4-n-hexyloxyphenyl)propiono-hydrazide (0.92 g) in tetrahydrofuran (25 ml) and pyridine (0.84 ml) was added a solution of 4-methoxycarbonylbenzoyl chloride (0.73 g) in tetrahydrofuran (10 ml) dropwise at 5° C. The reaction mixture was stirred for 1 hour and poured into ice-water. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 1-[3-(4-n-hexyloxyphenyl)propanoyl]-2-(4-methoxycarbonylbenzoyl)hydrazine (1.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[S:32]([NH2:36])([NH2:35])(=[O:34])=[O:33]>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([CH2:8][C:9]([NH:35][S:32]([NH2:36])(=[O:34])=[O:33])=[O:11])[CH:7]=1
Reactant: NS(N)(=O)=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(=O)O
Solvent: O=S(Cl)Cl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(=O)NS(N)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.7 %

Procedure:
A solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic acid (0.10 g, 0.21 mmol) in thionyl chloride (2 mL) was stirred at ambient temperature for two hours. The reaction was concentrated to dryness and the crude acid chloride was dissolved in 1,4-dioxane (4 mL) followed by addition of sulfamide (0.022 g, 0.23 mmol). The reaction was stirred at ambient temperature for 3 days. The reaction was concentrated and chromatographed on silica gel to give the title compound (0.014 g, LRMS: 525.1).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([O:10]C)=[O:9])[C:3]([O:5]C)=[O:4].[OH-].[Li+]>O1CCCC1.O>[CH3:1][CH:2]([CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)CC(C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CC(=O)O)C(=O)O
Temperature: 40 °C
Reaction time: 48 h

Procedure:
Commercially available dimethyl methylsuccinate (1.57 g, 9.8 mmol) was dissolved in a 3:1 mixed solvent of tetrahydrofuran and water, and lithium hydroxide (4 g, 98 mmol) was added and stirred for 2 days at 40° C. under reflux. After completion of the reaction was confirmed by TLC, the residue was distilled under reduced pressure to afford the title compound.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]/[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:39]3[CH:40]=[N:41][C:42]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:43][CH:44]=3)=[N:27][N:28]2[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C@:14]12[CH2:4][C@H:21]1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:39]3[CH:40]=[N:41][C:42]([N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)=[CH:43][CH:44]=3)=[N:27][N:28]2[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)/C(=C\c1ccc3c(-c4ccc(N5CCOCC5)nc4)nn(COCC[Si](C)(C)C)c3c1)C(=O)N2
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCOCC5)nc4)nn(COCC[Si](C)(C)C)c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of NaH (84 mg, 2.1 mmol) in DMF (5 mL) at 0° C. was added trimethylsulfoxonium iodide (154 mg, 0.70 mmol). The resulting mixture was stirred at rt for 30 min followed by the addition of (E)-5-Methoxy-3-((3-(6-morpholinopyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one in DMF (2 mL). The reaction mixture was then heated to 55° C. for 3 h. The reaction was cooled to 0° C. and quenched with saturated NH4Cl. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give yellow viscous oil. The crude product was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to yield a bright yellow powder, which was triturated with EtOAc to give the title compound as a pale yellow powder (93 mg, 44%). 1H NMR (400 MHz, CD3OD) δ 10.45 (br. s, 1H), 8.71 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.84 (s, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 6.73 (d, J=5.4 Hz, 1H), 6.56 (d, J=6.0 Hz, 1H), 5.86-5.75 (m, 3H), 3.71 (br s, 4H), 3.52 (br s, 4H), 3.40-3.16 (m, 6H), 2.42 (br. s, 1H), 2.00 (br. s, 1H), 0.79 (br s, 2H), −0.13 (s, 9H); MS ESI 598.4 [M+H]+, calcd for [C33H39N5O4Si+H]+ 598.28.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[F:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:40][C:39]1[CH:41]=[CH:42][C:36]([F:35])=[CH:37][CH:38]=1)=[O:27])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: Nc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)Nc3ccc(F)cc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-fluoroaniline (0.153 ml, 1.62 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the objective product as a solid material. The resultant material was recrystallized from hexane and ethyl acetate.
Reaction SMILES: CS([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=O)=O.[CH3:19][NH:20][CH3:21]>C(O)C>[CH3:19][N:20]([CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CNC
Reactant: CS(=O)(=O)CCCCC(=O)OCc1ccccc1
Solvent: CCO
Product: CN(C)CCCCC(=O)OCc1ccccc1
Yield: 69 %

Procedure:
Benzyl 5-(methanesulfonyl)pentanoate (1.39 g, 4.85 mmol) was allowed to react in a 5.6M solution of dimethylamine in ethanol (100 mL) for 20 hours. The solution was then concentrated in vacuo to dryness. The resulting brown oil was purified by column chromatography (column 10″L×1″W; eluted with a gradient of 100% dichloromethane→2%/0.5%→4%/0.5% MeOH/NH4OH in dichloromethane) to afford the product as a yellow oil (0.79 g, 69%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.O>O>[CH3:12][N:13]([CH3:20])[CH:14]1[CH2:19][CH2:18][N:17]([C:2]2[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:16][CH2:15]1
Reactant: CN(C)C1CCNCC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc([N+](=O)[O-])c(N)n2)CC1
Yield: 88 %

Procedure:
A solution of 6-chloro-3-nitro-pyridine-2-yl-amine (7 g, 40.6 mmol), dimethylpiperidine-4-yl-amine (5.7 g, 44.5 mmol), K2CO3 (6.39 g, 60.9 mmol) and DMF/water (4:1, 100 mL) was heated at 100° C. for 10 minutes in microwave reactor. After cooling, water was added and the resulting precipitate was collected by filtration and dried to give 6-(4-dimethylamino-piperidin-1-yl)-3-nitro-pyridin-2-yl-amine (9.48 g, 88%) as a yellow solid. 1H NMR (400 MHz, CD2Cl2) δ: 1.48 (m, 2H), 1.72 (m, 2H), 2.28 (s, 6H), 2.42 (m, 1H), 3.01 (m, 2H), 4.50 (m, 2H), 6.16 (d, J=9.54 Hz, 1H), 8.14 (d, J=9.54 Hz, 1H). HRMS: m/z 266.1628 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21]>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A slurry of amorphous ibandronic acid (4.6 g) in acetone (96 ml) was heated to reflux temperature. Sodium hydroxide (0.58 g, solid) was added, and the reaction mixture was stirred at reflux temperature for an additional 10 hours to obtain a pH of 3.35. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The white solid was filtered, washed with acetone (2×25 ml), and dried in a vacuum oven at 50° C. for 21 hours to give 4.5 g of ibandronate sodium crystal form Q.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=O)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.[CH3:17][C:18](=[O:23])[CH2:19][C:20](=[O:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=[C:19]([C:18](=[O:23])[CH3:17])[C:20](=[O:22])[CH3:21])=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2
Reactant: Cc1cc(=O)c2c(F)c(F)cc(C=O)c2o1
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)C(=Cc1cc(F)c(F)c2c(=O)cc(C)oc12)C(C)=O

Procedure:
250 mg (1.12 mmol) of 5,6-difluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 0.14 ml (1.34 mmol) of 2,4-pentanedione and 212.1 mg (1.12 mmol) of para-toluenesulfonic acid are heated in 100 ml of toluene under reflux with a water trap for 10 h. After cooling, 100 ml of ethyl acetate are added, and the reaction mixture is washed with water and with brine. Drying of the organic phase and concentration result in 269.7 mg (79% of theory) of the title compound as beige-coloured crystals.