Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C(Cl)(Cl)Cl>[N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:23]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1cccs1
Reactant: Oc1cccc2c1CCNC2CN1CCCC1
Solvent: ClC(Cl)Cl
Product: O=C(c1cccs1)N1CCc2c(O)cccc2C1CN1CCCC1

Procedure:
Prepared as Ex. N° 55, from 0.88 g (3.78 mmoles) of 1-(pyrrolidin-1-yl) methyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline and 0.83 g (5.66 mmoles) of 2-thiophene carbonyl chloride in 60 ml of dry chloroform, at -10° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:46][CH:45]([N:47]2[CH2:52][CH2:51][N:50]([CH3:53])[C@@H:49]([CH3:54])[CH2:48]2)[CH2:44]1>N1C=CC=CC=1>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N:43]4[CH2:46][CH:45]([N:47]5[CH2:52][CH2:51][N:50]([CH3:53])[C@@H:49]([CH3:54])[CH2:48]5)[CH2:44]4)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(C2CNC2)CCN1C
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Solvent: c1ccncc1
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(N4CC(N5CCN(C)[C@@H](C)C5)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (4.00 g 6.94 mmol) described in Production Example 1-1-6 and pyridine (100 mL) was added (2S)-4-(azetidin-3-yl)-1,2-dimethylpiperazine (2.35 g, 13.9 mmol) described in Production Example 4-3 at room temperature. The resultant mixture was stirred under reflux for 6 hours and 50 minutes. The reaction mixture was cooled to room temperature, and then concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (methanol), and then purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (2.93 g, yield: 58%).
Reaction SMILES: [H-].[Na+:2].[Cl:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1>CN(C)C=O>[Cl:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])[C:8]([O-:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1.[Na+:2]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1[O-]
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (2 g.) in dry dimethyl formamide (20 ml.) was added dropwise a solution of 4-chloromethyl-2, 6-di-tert-butylphenol (10 g.) in dimethyl formamide (40 ml.) at 25°-30° C. The mixture was stirred for 30 minutes, during which gas evolution ceased, so as to produce a solution of sodium 4-chloromethyl-2, 6-di-tert-butylphenoxide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=1[C:22]#[N:23].CCN(C(C)C)C(C)C>CC#N>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:20]([CH2:19][N:9]([CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[C:21]([CH:24]=1)[C:22]#[N:23]
Reactant: Cc1cccnc1CNC(C)c1ccccn1
Reactant: COc1ccc(CBr)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN(Cc2ncccc2C)C(C)c2ccccn2)c(C#N)c1

Procedure:
Using General Procedure A: Reaction of (3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amine, 2-bromomethyl-5-methoxybenzonitrile (Ando, K. et al. Bull. Chem. Soc. Jpn. 1980, 53, 2885-2890), DIPEA and KI in CH3CN gave 5-methoxy-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-benzonitrile as an orange oil. 1H NMR (CDCl3) δ 1.60 (d, 3H, J=6.9 Hz), 2.08 (s, 3H), 3.73 (d, 1H, J=15.0 Hz), 3.74 (d, 1H, J=12.3 Hz), 3.78 (s, 3H), 3.92 (d 1H, J=12.3 Hz), 3.93 (d, 1H, J=15.0 Hz), 4.03 (q, 1H, J=6.9 Hz), 6.95-7.04 (m, 3H), 7.16 (ddd, 1H, J=7.5, 5.0, 1.0 Hz), 7.29 (t, 2H, J=6.6 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.65 (td, 1H, J=7.7, 1.8 Hz), 8.32 (dd, 1H, J=4.8, 1.2 Hz), 8.58 (dd, 1H, J=4.8, 0.9 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][C:17]#[N:18]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1
Reactant: c1ccc(CCN2CCNCC2)nc1
Reactant: N#CCBr
Product: N#CCN1CCN(CCc2ccccn2)CC1

Procedure:
The title compound is synthesized by coupling of 1-(2-Pyridin-2-yl-ethyl)-piperazine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=231.2: CtRet=2.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:24][CH2:23][CH2:22][N:12]2[C:13]=1[C:14]1[N:15]=[N:16][C:17]([NH:20][NH2:21])=[CH:18][CH:19]=1.[N:25]([CH2:28][CH3:29])=[C:26]=S>CN(C1C=CN=CC=1)C.CCO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:24][CH2:23][CH2:22][N:12]2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]2[N:16]([C:26]([NH:25][CH2:28][CH3:29])=[N:21][N:20]=2)[N:15]=1
Reactant: CCN=C=S
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3n2CCC3)nn1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCNc1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Temperature: 75 °C
Yield: 17.2 %

Procedure:
2-(2,4-Difluorophenyl)-3-(6-hydrazinylpyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (0.200 g, 0.609 mmol, Example #35, Step E) and isothiocyanatoethane (0.085 g, 0.975 mmol) were added to EtOH (3 mL). The suspension was heated to about 75° C. for about 3 h. DMAP (0.138 g, 0.670 mmol) was added and the solution was heated in a CEM® microwave at about 150° C. for about 10 min (250 psi maximum pressure, 10 min ramp, 300 max watts). Solvent was removed in vacuo and the material was purified by flash chromatography using MeOH/DCM (0-6% gradient) and then further purified by RP-HPLC (Table 1, Method m). The ACN was removed and the resulting precipitate was collected to afford the title compound (0.040 g, 17%): LC/MS (Table 1, Method g) Rt=1.77 min; MS m/z: 382.2 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:15][C:14]=1[C:25]1[C:26]([S:31]([N:34]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[C:42]=2[CH3:47])COCCOC)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.CC1C(C)=C(NS(C2C(C3C=CC(C4N=CC=CN=4)=CC=3C=O)=CC=CC=2)(=O)=O)ON=1>CN(C)C=O.O>[CH3:46][C:43]1[C:42]([CH3:47])=[C:41]([NH:34][S:31]([C:26]2[C:25]([C:14]3[CH:15]=[CH:16][C:17]([C:19]4[N:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:18][C:13]=3[CH2:12][N:4]3[CH2:5][CH2:6][C:2]([CH3:8])([CH3:1])[C:3]3=[O:7])=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:33])=[O:32])[O:45][N:44]=1
Reactant: CC1(C)CCNC1=O
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncccn2)cc1CBr
Agent: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncccn3)cc2C=O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncccn3)cc2CN2CCC(C)(C)C2=O)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of the 3,3-dimethyl-2-pyrrolidinone so prepared (0.033 g, 0.29 mmol) in 1 mL of dimethylformamide ("DMF"), NaH (60% suspension in mineral oil, 0.015 g, 0.36 mmol) was added and the mixture was stirred at room temperature under argon for 10 minutes. 2'-(Bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)[1,1'-biphenyl]-2-sulfonamide (prepared as described in Step A of Example 14, except that the title compound of Step F of Example 11 was employed in place of N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)[1,1'-biphenyl]-2-sulfonamide; 0.085 g, 0.145 mmol) was then added and the mixture was stirred for 3 hrs. The mixture was then added to 50 mL water and the solution was extracted with 3×25 mL EtOAc. The combined organic extracts were washed with water and dried and evaporated to afford 0.086 g (95%) of the title compound of this step as a colorless gum.
Reaction SMILES: [OH:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[C:41](=O)(O)[O-].[Na+].CI>CN(C=O)C>[CH3:41][O:15][C:14](=[O:16])[C:13]1[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:40][CH:39]=2)[CH:12]=1
Reactant: O=C([O-])O
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(O)cc2)cc(C(=O)O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(O)cc2)cc(C(=O)OC)c1
Yield: 96.7 %

Procedure:
A mixture of 0.30 g (0.54 mmol) of 3-[3-(4-hydroxyphenoxy) propoxy]-5-(octadecyloxy)benzoic acid, 0.14 g (1.62 mmol) of sodium bicarbonate and 0.67 ml (10.8 mmol) of methyl iodide in 5 ml of DMF was stirred and heated at 40° for 48 hours. The solvent was removed at reduced pressure, the residue was extracted with ethyl acetate and the extract was washed with water. The dried extract was concentrated to a solid which was triturated with hexane and filtered to give 0.298 g (97% yield, mp 88°-90°) of 3-[3-(4-hydroxyphenoxy)propoxy]-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: C(=O)(OC(Cl)(Cl)Cl)[O:2][C:3]([Cl:6])(Cl)Cl.N1C=CC=CC=1.[CH3:19][NH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1>O1CCCC1>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([N:20]([CH3:19])[C:3]([Cl:6])=[O:2])=[N:22][CH:23]=1)#[N:26]
Reactant: CNc1ccc(C#N)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C(=O)Cl)c1ccc(C#N)cn1

Procedure:
To a solution of bis(trichloromethyl) carbonate (50 mg, 0.17 mmol) in tetrahydrofuran (2.0 mL) was added pyridine (0.04 mL, 0.510 mmol) dropwise under ice-cooling. After stirring under ice-cooling for 30 min, 6-(methylamino)nicotinonitrile (68 mg, 0.510 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. The precipitated solid was filtered off. The filtrate containing (5-cyanopyridin-2-yl)(methyl)carbamic chloride (I-28) was directly used for next step.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([N+:9]([O-])=O)=[CH:7][N:6]=[CH:5]2)[CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([N:4]2[C:8]([NH2:9])=[CH:7][N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cncn1C1CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cncn1C1CC1
Yield: 41.4 %

Procedure:
A methanol (15 ml) solution containing 1-cyclopropyl-5-nitro-1H-imidazole (60 mg) was prepared and subjected to hydrogenation reaction (80° C.; 50 bar; flow rate: 2 ml/min; 10% Pd/C) using H-cube™. Thereafter, the solvent was distilled away under reduced pressure, and a purple solid of 1-cyclopropyl-1H-imidazol-5-amine (20 mg) was thus obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:18]1[CH2:27][CH2:26][CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:19]1>CS(C)=O>[CH3:8][C:7]1[C:2]([N:18]2[CH2:27][CH2:26][CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:19]2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1CCN(c2ncc([N+](=O)[O-])cc2C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 2-chloro-3-methyl-5-nitropyridine (1.73 g, 10.00 mmol) in DMSO (20 mL) was added sodium carbonate (5.30 g, 50.00 mmol) followed by methyl isonipecotate (1.35 mL, 10.00 mmol). The reaction mixture was heated to 60° C. for 110 minutes. The reaction mixture was left to stand at room temperature overnight. A further aliquot of methyl isonipecotate (3.33 mmol, 476 mg, 450 μL) was added and heating resumed at 60° C. for 100 mins. The reaction mixture was poured onto ice water and the suspension was filtered, washed with water (4×75 mL) and dried under vacuum to leave a yellow powder; (2.43 g, 87% yield). This was used in the next stage without further purification. 1H NMR δ 1.61-1.74 (m, 2H), 1.91-2.10 (m, 2H), 2.31 (s, 3H), 2.61-2.73 (m, 1H), 2.94-3.09 (m, 2H), 3.61 (s, 3H), 3.83-3.98 (m, 2H), 8.19 (d, 1H), 8.86 (d, 1H). MS m/e MH+ 280.18.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12](/[CH:16]=[CH:17]/[C:18]#[N:19])=[CH:11][C:10]=2[CH3:20])[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>C(O)(C)C>[CH3:20][C:10]1[CH:11]=[C:12](/[CH:16]=[CH:17]/[C:18]#[N:19])[CH:13]=[C:14]([CH3:15])[C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[N:7]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CC(C)O
Product: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Nc2ccc(C#N)cc2)n1
Temperature: 82.5 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
To a mixture of (E)-3-(4-(2-chloropyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile (40 gm), 4-aminobenzonitrile (17 gm), isopropanol (400 ml) and p-toluenesulfonic acid (20 ml) were added at room temperature. The reaction mixture was then heated to 80 to 85° C. and stirred for 4 hours. The reaction mass was then cooled to 0° C. and pH was adjusted to 10 to 11 with aqueous ammonia solution. The separated solid was filtered and then dried to provide 40 gm of rilpivirine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:25]3[C:20](=[C:21]([OH:28])[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[CH:19]=[N:18]2)[CH:5]=[C:6]([F:16])[C:7]=1[O:8]CC1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:25]3[C:20](=[C:21]([OH:28])[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[CH:19]=[N:18]2)[CH:5]=[C:6]([F:16])[C:7]=1[OH:8]
Reactant: N#Cc1cc(O)c2cnn(-c3cc(F)c(OCc4ccccc4)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1cc(O)c2cnn(-c3cc(F)c(O)c(F)c3)c2c1
Yield: 50.6 %

Procedure:
A solution of 1-{3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}-4-hydroxy-1H-indazole-6-carbonitrile (D37) (610 mg, 1.617 mmol) in ethyl acetate (50 mL) was passed through the H-cube over a 10% palladium on charcoal catalyst at room temperature and pressure. The filtrate was concentrated and then triturated with dichloromethane and collected by filtration to yield the desired product (E20) (235 mg).
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])[CH2:2][CH3:3].[C:12]1([CH2:18]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]1([CH2:18][N:6]2[C:5](=[O:11])[CH:4]([CH2:1][CH2:2][CH3:3])[NH:8][S:7]2(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCC1NS(=O)(=O)NC1=O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Yield: 39.2 %

Procedure:
To a mixture of 4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5.0 g, 28.25 mmol) suspended in 150 ml of toluene was added phenylmethyl bromide (5.32 g, 31.03 mmol) and tetrabutylammonium bromide (0.9 g, 0.28 mmol). The resulting mixture was refluxed for 19 hours, cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford 2.97 g (39%) of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IX: R1 =H; R2 =propyl) as a solid, m.p., 63.5°-65.5° C.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1>C1COCC1.CN(C=O)C.O>[Cl:42][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][CH:39]=1
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Cl)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
Dissolved 428 mg (5.09 mmol) 2-butynoic acid in 40 ml THF and chilled to 0° C. under N2. Added 560 μl (5.09 mmol) N-methylmorpholine and 662 μl (5.09 mmol) isobutyl chloroformate and stirred for 10 minutes. Added dropwise a solution of 1.00 g (3.39 mmol) 6-amino-4-[(3-chlorophenyl)amino]-3-quinolinecarbonitrile in 2 ml DMF and 20 ml THF. Removed ice bath at 15 minutes and stirred at 25° C. overnight. Stripped solvent, slurried residue with water and collected solids. Boiled in ethyl acetate, collected and dried in vacuo, giving 975 mg of yellow solid: mass spectrum (electrospray m/e): M+H=361.1, 363.2.
Reaction SMILES: [N:1]1[C:11]2[C@@H:10]3[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C@H:9]3[CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[Cl:36].[OH-].[Na+]>ClCCl>[Cl:29][C:30]1[CH:31]=[C:32]([S:37]([N:7]2[CH2:8][C@@H:9]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][C@H:10]3[C:11]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)(=[O:38])=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNCc3cccnc3[C@@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H]2CN(S(=O)(=O)c3ccc(Cl)c(Cl)c3)Cc3cccnc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Example 334B (100 mg, 0.34 mmol) and triethylamine (0.097 mL, 0.69 mmol) in dichloromethane (2 mL) was stirred at ambient temperature for 10 minutes. 3,4-Dichlorobenzene-1-sulfonyl chloride (0.52 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred at room temperature overnight. A 10% NaOH solution (2 mL) was added; the dichloromethane layer was separated, treated with water (2 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[N:5]=[C:4]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[S:22][CH2:23][CH:3]12.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl.O>CS(C)=O>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:14][CH:15]=2)[N:5]=[C:4]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[S:22][CH:23]=[C:3]12
Reactant: O=C(O)c1ccc(N2N=C3c4ccccc4SCC3C2=O)cc1
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 4-(3-Oxo-3a,4-dihydro-3H-thiochromeno[4,3-c]pyrazol-2-yl)-benzoic acid (250 mg, 0.77 mmol) was dissolved in dimethyl sulphoxide (6 ml). O-Chloranil (189 mg, 0.77 mmol) was added and the mixture was stirred at room temperature overnight. Water (20 ml) was added and the solids were collected by filtration and washed with water. The filter cake was triturated with toluene, filtered and dried under vacuum. The title compound was isolated as a dark brown solid (230 mg, 0.71 mmol, 92%). LCMS: m/z 323 [M+H]+
Reaction SMILES: Cl[CH2:2][CH:3]([O:6][CH3:7])[O:4][CH3:5].[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>O>[CH3:5][O:4][CH:3]([O:6][CH3:7])[CH2:2][NH:14][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(CCl)OC
Reactant: NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(CNC1CCCCC1)OC
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-1,1-dimethoxyethane (206 mL) was treated with cyclohexanamine (575 mL) and the mixture was heated at 120° C. for 24 h under an atmosphere of nitrogen before being cooled to room temperature. A solution of sodium hydroxide (100 g) in 400 mL water was added, the mixture was stirred at room temperature for 10 min and then the layers were separated. The organic fraction was purified by distillation under reduced pressure (b.p. 105-107° C., 13 mm Hg) to give the title compound as a colourless oil (280 g). 1H NMR (400 MHz, CDCl3) δ 4.46 (t, J=5.5 Hz, 1H), 3.38 (s, 6H), 2.75 (d, J=5.6 Hz, 2H), 2.45-2.35 (m, 1H), 1.92-1.57 (m, 5H), 1.31-1.00 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][OH:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a stirred solution of [5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol (7.2 g, 0.021 mol) in THF (125 mL) and triethylamine (TEA) (4.6 mL, 0.033 mol) was added methanesulfonyl chloride (2.5 mL, 0.031 mol). The reaction mixture was stirred at 45° C. for 4 h. The reaction mixture was cooled to rt, quenched with H2O (75 mL) then washed with EtOAc (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to oil. This crude pyrazole mesylate was used in the next step without further purification. HPLC: Rt=10.03 (Method E). MS (ES+): mass calculated for C18H18Cl2N2O4S, 427.30; m/z found 428.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:9]([OH:12])([OH:11])=[O:10])([P:5]([OH:8])([OH:7])=[O:6])[OH:4].O.[Na].[OH-].[Na+:18].C(CN)CC(P(O)(O)=O)(P(O)(O)=O)O>O.C(O)C>[CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:5]([O-:7])([OH:8])=[O:6])([P:9]([OH:12])([OH:11])=[O:10])[OH:4].[Na+:18]
Reactant: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O
Reaction time: 15 h

Procedure:
In accordance with the aspects of this invention wherein alendronic acid monohydrate is converted to,alendronate sodium, alendronic acid monohydrate as prepared by any of the known methods is added to an alkanol, preferably ethanol, together with a sodium base, preferably sodium hydroxide, and a desired amount of water. The amount of water depends upon the crystal form that is desired. The molar ratio of sodium base to alendronic acid is 1:1. The reaction mixture is boiled under reflux while stirring vigorously for approximately 15 hours, until the pH of the liquid phase remains constant (approx. pH 7). Crystalline alendronate sodium is then isolated, preferably by filtration after cooling to ambient temperature followed by washing with absolute ethanol, washing with absolute ether and drying overnight in a vacuum oven at ambient temperature and at a pressure of 10 mm to 15 mm of mercury.